Updated on 2022/12/09

写真a

 
SUMIYAMA Kenta
 
Organization
Graduate School of Bioagricultural Sciences Department of Animal Sciences Professor
Graduate School
Graduate School of Bioagricultural Sciences
Undergraduate School
School of Agricultural Sciences Department of Bioresource Sciences
Title
Professor
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Research Interests 19

  1. 遺伝子発現制御

  2. 遺伝

  3. 進化

  4. 発生

  5. 比較ゲノム解析

  6. 分子進化

  7. トランスポゾン

  8. トランスジェニックマウス

  9. genome editing

  10. エンハンサー

  11. transposon

  12. transgenic mouse

  13. exaptation

  14. evolution

  15. evo-devo

  16. evo-devo

  17. CRISPR/Cas9

  18. co-option

  19. cis-element

Research Areas 4

  1. Life Science / Evolutionary biology  / molecular evolution of the gene regulatory system

  2. Life Science / Developmental biology  / Developmental Gene Regulation

  3. Life Science / Developmental biology  / Evolutionary developmental biology

  4. Life Science / Laboratory animal science  / Developmental Genetic Engineering

Research History 8

  1. Nagoya University   Professor

    2022.9

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    Country:Japan

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  2. RIKEN Center for Biosystems Dynamics Research (BDR)   Laboratory for Mouse Genetic Engineering   Team leader

    2020.4

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  3. RIKEN Center for Biosystems Dynamics Research (BDR)   Laboratory for Mouse Genetic Engineering   Unit Leader

    2018.4 - 2020.3

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  4. RIKEN   Quantitative Biology Center (QBiC), Cell Design Research Core, Laboratory for Mouse Genetic Engineering   Unit leader

    2013.6 - 2018.3

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  5. National Institute of Genetics   Assistant Professor

    2007.4 - 2013.9

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  6. National Institute of Genetics   Assistant

    2003.3 - 2007.3

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  7. Yale大学 Molecular, Cellular and Developmental Biology   博士研究員

    1998.5 - 2003.2

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  8. National Institute of Genetics

    1996.4 - 1998.5

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Education 1

  1. 東京大学大学院   理学系研究科   生物科学

    1991.4 - 1996.3

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    Country: Japan

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Professional Memberships 8

  1. THE GENETICS SOCIETY OF JAPAN

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  2. SOCIETY OF EVOLUTIONARY STUDIES, JAPAN

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  3. JAPAN SOCIETY FOR CELL BIOLOGY

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  4. JAPANESE SOCIETY OF DEVELOPMENTAL BIOLOGISTS

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  5. JAPANESE ASSOCIATION FOR LABORATORY ANIMAL SCIENCE

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  6. THE MOLECULAR BIOLOGY SOCIETY OF JAPAN

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  7. THE ANTHROPOLOGICAL SOCIETY OF NIPPON

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  8. 日本ゲノム編集学会

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Committee Memberships 2

  1. 日本進化学会   広報  

    2010 - 2013   

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    Committee type:Academic society

    進化学会

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  2. 日本進化学会   会計監査  

    2008 - 2009   

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    Committee type:Academic society

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Awards 1

  1. 第17回(2012年度)日本細胞生物学会論文賞(CSF Award)

    2013.6  

    隅山 健太

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Papers 69

  1. Generation of transgenic mice expressing a FRET biosensor, SMART, that responds to necroptosis. Reviewed International journal

    Shin Murai, Kanako Takakura, Kenta Sumiyama, Kenta Moriwaki, Kenta Terai, Sachiko Komazawa-Sakon, Takao Seki, Yoshifumi Yamaguchi, Tetuo Mikami, Kimi Araki, Masaki Ohmuraya, Michiyuki Matsuda, Hiroyasu Nakano

    Communications biology   Vol. 5 ( 1 ) page: 1331 - 1331   2022.12

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    Language:English   Publishing type:Research paper (scientific journal)  

    Necroptosis is a regulated form of cell death involved in various pathological conditions, including ischemic reperfusion injuries, virus infections, and drug-induced tissue injuries. However, it is not fully understood when and where necroptosis occurs in vivo. We previously generated a Forster resonance energy transfer (FRET) biosensor, termed SMART (the sensor for MLKL activation by RIPK3 based on FRET), which monitors conformational changes of MLKL along with progression of necroptosis in human and murine cell lines in vitro. Here, we generate transgenic (Tg) mice that express the SMART biosensor in various tissues. The FRET ratio is increased in necroptosis, but not apoptosis or pyroptosis, in primary cells. Moreover, the FRET signals are elevated in renal tubular cells of cisplatin-treated SMART Tg mice compared to untreated SMART Tg mice. Together, SMART Tg mice may provide a valuable tool for monitoring necroptosis in different types of cells in vitro and in vivo.

    DOI: 10.1038/s42003-022-04300-0

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  2. Distinct phosphorylation states of mammalian CaMKIIβ control the induction and maintenance of sleep Reviewed

    Daisuke Tone, Koji L. Ode, Qianhui Zhang, Hiroshi Fujishima, Rikuhiro G. Yamada, Yoshiki Nagashima, Katsuhiko Matsumoto, Zhiqing Wen, Shota Y. Yoshida, Tomoki T. Mitani, Yuki Arisato, Rei-ichiro Ohno, Maki Ukai-Tadenuma, Junko Yoshida Garçon, Mari Kaneko, Shoi Shi, Hideki Ukai, Kazunari Miyamichi, Takashi Okada, Kenta Sumiyama, Hiroshi Kiyonari, Hiroki R. Ueda

    PLOS Biology   Vol. 20 ( 10 ) page: e3001813 - e3001813   2022.10

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    Publishing type:Research paper (scientific journal)   Publisher:Public Library of Science (PLoS)  

    The reduced sleep duration previously observed in Camk2b knockout mice revealed a role for Ca<sup>2+</sup>/calmodulin-dependent protein kinase II (CaMKII)β as a sleep-promoting kinase. However, the underlying mechanism by which CaMKIIβ supports sleep regulation is largely unknown. Here, we demonstrate that activation or inhibition of CaMKIIβ can increase or decrease sleep duration in mice by almost 2-fold, supporting the role of CaMKIIβ as a core sleep regulator in mammals. Importantly, we show that this sleep regulation depends on the kinase activity of CaMKIIβ. A CaMKIIβ mutant mimicking the constitutive-active (auto)phosphorylation state promotes the transition from awake state to sleep state, while mutants mimicking subsequent multisite (auto)phosphorylation states suppress the transition from sleep state to awake state. These results suggest that the phosphorylation states of CaMKIIβ differently control sleep induction and maintenance processes, leading us to propose a “phosphorylation hypothesis of sleep” for the molecular control of sleep in mammals.

    DOI: 10.1371/journal.pbio.3001813

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  3. The regulatory landscape of the Dlx gene system in branchial arches: Shared characteristics among Dlx bigene clusters and evolution. Reviewed

    Kenta Sumiyama, Akira Tanave

    Development, growth & differentiation   Vol. 62 ( 5 ) page: 355 - 362   2020.6

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    The mammalian Dlx genes encode homeobox-type transcription factors and are physically organized as convergent bigene clusters. The paired Dlx genes share tissue specificity in the expression profile. Genetic regulatory mechanisms, such as intergenic enhancer sharing between paired Dlx genes, have been proposed to explain this conservation of bigene structure. All mammalian Dlx genes have expression and function in developing craniofacial structures, especially in the first and second pharyngeal arches (branchial arches). Each Dlx cluster (Dlx1/2, Dlx3/4, and Dlx5/6) has overlapping, nested expression in the branchial arches which is called the "Dlx code" and plays a key role in organizing craniofacial structure and evolution. Here we summarize cis-regulatory studies on branchial arch expression of the three Dlx bigene clusters and show some shared characteristics among the clusters, including cis-regulatory motifs, TAD (Topologically Associating Domain) boundaries, CTCF loops, and distal enhancer landscapes, together with a molecular condensate model for activation of the Dlx bigene cluster.

    DOI: 10.1111/dgd.12671

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  4. FRET-assisted photoactivation of flavoproteins for in vivo two-photon optogenetics. Reviewed International journal

    Tomoaki Kinjo, Kenta Terai, Shoichiro Horita, Norimichi Nomura, Kenta Sumiyama, Kaori Togashi, So Iwata, Michiyuki Matsuda

    Nature methods   Vol. 16 ( 10 ) page: 1029 - 1036   2019.10

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    Optical dimerizers have been developed to untangle signaling pathways, but they are of limited use in vivo, partly due to their inefficient activation under two-photon (2P) excitation. To overcome this problem, we developed Förster resonance energy transfer (FRET)-assisted photoactivation, or FRAPA. On 2P excitation, mTagBFP2 efficiently absorbs and transfers the energy to the chromophore of CRY2. Based on structure-guided engineering, a chimeric protein with 40% FRET efficiency was developed and named 2P-activatable CRY2, or 2paCRY2. 2paCRY2 was employed to develop a RAF1 activation system named 2paRAF. In three-dimensionally cultured cells expressing 2paRAF, extracellular signal-regulated kinase (ERK) was efficiently activated by 2P excitation at single-cell resolution. Photoactivation of ERK was also accomplished in the epidermal cells of 2paRAF-expressing mice. We further developed an mTFP1-fused LOV domain that exhibits efficient response to 2P excitation. Collectively, FRAPA will pave the way to single-cell optical control of signaling pathways in vivo.

    DOI: 10.1038/s41592-019-0541-5

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  5. Next-generation human genetics for organism-level systems biology. Reviewed International journal

    Hideki Ukai, Kenta Sumiyama, Hiroki R Ueda

    Current opinion in biotechnology   Vol. 58   page: 137 - 145   2019.8

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    Systems-biological approaches, such as comprehensive identification and analysis of system components and networks, are necessary to understand design principles of human physiology and pathology. Although reverse genetics using mouse models have been used previously, it is a low throughput method because of the need for repetitive crossing to produce mice having all cells of the body with knock-out or knock-in mutations. Moreover, there are often issues from the interspecific gap between humans and mice. To overcome these problems, high-throughput methods for producing knock-out or knock-in mice are necessary. In this review, we describe 'next-generation' human genetics, which can be defined as high-throughput mammalian genetics without crossing to knock out human-mouse ortholog genes or to knock in genetically humanized mutations.

    DOI: 10.1016/j.copbio.2019.03.003

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  6. Muscarinic Acetylcholine Receptors Chrm1 and Chrm3 Are Essential for REM Sleep. Reviewed International journal

    Yasutaka Niwa, Genki N Kanda, Rikuhiro G Yamada, Shoi Shi, Genshiro A Sunagawa, Maki Ukai-Tadenuma, Hiroshi Fujishima, Naomi Matsumoto, Koh-Hei Masumoto, Mamoru Nagano, Takeya Kasukawa, James Galloway, Dimitri Perrin, Yasufumi Shigeyoshi, Hideki Ukai, Hiroshi Kiyonari, Kenta Sumiyama, Hiroki R Ueda

    Cell reports   Vol. 24 ( 9 ) page: 2231 - 2247   2018.8

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    Sleep regulation involves interdependent signaling among specialized neurons in distributed brain regions. Although acetylcholine promotes wakefulness and rapid eye movement (REM) sleep, it is unclear whether the cholinergic pathway is essential (i.e., absolutely required) for REM sleep because of redundancy from neural circuits to molecules. First, we demonstrate that synaptic inhibition of TrkA+ cholinergic neurons causes a severe short-sleep phenotype and that sleep reduction is mostly attributable to a shortened sleep duration in the dark phase. Subsequent comprehensive knockout of acetylcholine receptor genes by the triple-target CRISPR method reveals that a similar short-sleep phenotype appears in the knockout of two Gq-type acetylcholine receptors Chrm1 and Chrm3. Strikingly, Chrm1 and Chrm3 double knockout chronically diminishes REM sleep to an almost undetectable level. These results suggest that muscarinic acetylcholine receptors, Chrm1 and Chrm3, are essential for REM sleep.

    DOI: 10.1016/j.celrep.2018.07.082

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  7. Easy and efficient production of completely embryonic-stem-cell-derived mice using a micro-aggregation device. Reviewed

    Sumiyama K, Matsumoto N, Garçon-Yoshida J, Ukai H, Ueda HR, Tanaka Y

    PloS one   Vol. 13 ( 9 ) page: e0203056   2018

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    DOI: 10.1371/journal.pone.0203056

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  8. Mammalian Reverse Genetics without Crossing Reveals Nr3a as a Short-Sleeper Gene. Reviewed International journal

    Genshiro A Sunagawa, Kenta Sumiyama, Maki Ukai-Tadenuma, Dimitri Perrin, Hiroshi Fujishima, Hideki Ukai, Osamu Nishimura, Shoi Shi, Rei-Ichiro Ohno, Ryohei Narumi, Yoshihiro Shimizu, Daisuke Tone, Koji L Ode, Shigehiro Kuraku, Hiroki R Ueda

    Cell reports   Vol. 14 ( 3 ) page: 662 - 677   2016.1

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    The identification of molecular networks at the system level in mammals is accelerated by next-generation mammalian genetics without crossing, which requires both the efficient production of whole-body biallelic knockout (KO) mice in a single generation and high-performance phenotype analyses. Here, we show that the triple targeting of a single gene using the CRISPR/Cas9 system achieves almost perfect KO efficiency (96%-100%). In addition, we developed a respiration-based fully automated non-invasive sleep phenotyping system, the Snappy Sleep Stager (SSS), for high-performance (95.3% accuracy) sleep/wake staging. Using the triple-target CRISPR and SSS in tandem, we reliably obtained sleep/wake phenotypes, even in double-KO mice. By using this system to comprehensively analyze all of the N-methyl-D-aspartate (NMDA) receptor family members, we found Nr3a as a short-sleeper gene, which is verified by an independent set of triple-target CRISPR. These results demonstrate the application of mammalian reverse genetics without crossing to organism-level systems biology in sleep research.

    DOI: 10.1016/j.celrep.2015.12.052

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  9. The African coelacanth genome provides insights into tetrapod evolution. Reviewed International journal

    Chris T Amemiya, Jessica Alföldi, Alison P Lee, Shaohua Fan, Hervé Philippe, Iain Maccallum, Ingo Braasch, Tereza Manousaki, Igor Schneider, Nicolas Rohner, Chris Organ, Domitille Chalopin, Jeramiah J Smith, Mark Robinson, Rosemary A Dorrington, Marco Gerdol, Bronwen Aken, Maria Assunta Biscotti, Marco Barucca, Denis Baurain, Aaron M Berlin, Gregory L Blatch, Francesco Buonocore, Thorsten Burmester, Michael S Campbell, Adriana Canapa, John P Cannon, Alan Christoffels, Gianluca De Moro, Adrienne L Edkins, Lin Fan, Anna Maria Fausto, Nathalie Feiner, Mariko Forconi, Junaid Gamieldien, Sante Gnerre, Andreas Gnirke, Jared V Goldstone, Wilfried Haerty, Mark E Hahn, Uljana Hesse, Steve Hoffmann, Jeremy Johnson, Sibel I Karchner, Shigehiro Kuraku, Marcia Lara, Joshua Z Levin, Gary W Litman, Evan Mauceli, Tsutomu Miyake, M Gail Mueller, David R Nelson, Anne Nitsche, Ettore Olmo, Tatsuya Ota, Alberto Pallavicini, Sumir Panji, Barbara Picone, Chris P Ponting, Sonja J Prohaska, Dariusz Przybylski, Nil Ratan Saha, Vydianathan Ravi, Filipe J Ribeiro, Tatjana Sauka-Spengler, Giuseppe Scapigliati, Stephen M J Searle, Ted Sharpe, Oleg Simakov, Peter F Stadler, John J Stegeman, Kenta Sumiyama, Diana Tabbaa, Hakim Tafer, Jason Turner-Maier, Peter van Heusden, Simon White, Louise Williams, Mark Yandell, Henner Brinkmann, Jean-Nicolas Volff, Clifford J Tabin, Neil Shubin, Manfred Schartl, David B Jaffe, John H Postlethwait, Byrappa Venkatesh, Federica Di Palma, Eric S Lander, Axel Meyer, Kerstin Lindblad-Toh

    Nature   Vol. 496 ( 7445 ) page: 311 - 6   2013.4

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    The discovery of a living coelacanth specimen in 1938 was remarkable, as this lineage of lobe-finned fish was thought to have become extinct 70 million years ago. The modern coelacanth looks remarkably similar to many of its ancient relatives, and its evolutionary proximity to our own fish ancestors provides a glimpse of the fish that first walked on land. Here we report the genome sequence of the African coelacanth, Latimeria chalumnae. Through a phylogenomic analysis, we conclude that the lungfish, and not the coelacanth, is the closest living relative of tetrapods. Coelacanth protein-coding genes are significantly more slowly evolving than those of tetrapods, unlike other genomic features. Analyses of changes in genes and regulatory elements during the vertebrate adaptation to land highlight genes involved in immunity, nitrogen excretion and the development of fins, tail, ear, eye, brain and olfaction. Functional assays of enhancers involved in the fin-to-limb transition and in the emergence of extra-embryonic tissues show the importance of the coelacanth genome as a blueprint for understanding tetrapod evolution.

    DOI: 10.1038/nature12027

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  10. Theria-Specific Homeodomain and cis-Regulatory Element Evolution of the Dlx3-4 Bigene Cluster in 12 Different Mammalian Species Reviewed

    Kenta Sumiyama, Tsutomu Miyake, Jane Grimwood, Andrew Stuart, Mark Dickson, Jeremy Schmutz, Frank H. Ruddle, Richard M. Myers, Chris T. Amemiya

    JOURNAL OF EXPERIMENTAL ZOOLOGY PART B-MOLECULAR AND DEVELOPMENTAL EVOLUTION   Vol. 318B ( 8 ) page: 639 - 650   2012.12

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:WILEY-BLACKWELL  

    The mammalian Dlx3 and Dlx4 genes are configured as a bigene cluster, and their respective expression patterns are controlled temporally and spatially by cis-elements that largely reside within the intergenic region of the cluster. Previous work revealed that there are conspicuously conserved elements within the intergenic region of the Dlx34 bigene clusters of mouse and human. In this paper we have extended these analyses to include 12 additional mammalian taxa (including a marsupial and a monotreme) in order to better define the nature and molecular evolutionary trends of the coding and non-coding functional elements among morphologically divergent mammals. Dlx34 regions were fully sequenced from 12 divergent taxa of interest. We identified three theria-specific amino acid replacements in homeodomain of Dlx4 gene that functions in placenta. Sequence analyses of constrained nucleotide sites in the intergenic non-coding region showed that many of the intergenic conserved elements are highly conserved and have evolved slowly within the mammals. In contrast, a branchial arch/craniofacial enhancer I37-2 exhibited accelerated evolution at the branch between the monotreme and therian common ancestor despite being highly conserved among therian species. Functional analysis of I37-2 in transgenic mice has shown that the equivalent region of the platypus fails to drive transcriptional activity in branchial arches. These observations, taken together with our molecular evolutionary data, suggest that theria-specific episodic changes in the I37-2 element may have contributed to craniofacial innovation at the base of the mammalian lineage. J. Exp. Zool. (Mol. Dev. Evol.) 9999B:639650, 2012. (c) 2012 Wiley Periodicals, Inc.

    DOI: 10.1002/jez.b.22469

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  11. Live Imaging of Protein Kinase Activities in Transgenic Mice Expressing FRET Biosensors Reviewed

    Yuji Kamioka, Kenta Sumiyama, Rei Mizuno, Yoshiharu Sakai, Eishu Hirata, Etsuko Kiyokawa, Michiyuki Matsuda

    CELL STRUCTURE AND FUNCTION   Vol. 37 ( 1 ) page: 65 - 73   2012

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:JAPAN SOC CELL BIOLOGY  

    Genetically-encoded biosensors based on the principle of Forster resonance energy transfer (FRET) have been widely used in biology to visualize the spatiotemporal dynamics of signaling molecules. Despite the increasing multitude of these biosensors, their application has been mostly limited to cultured cells with transient biosensor expression, due to particular difficulties in the development of transgenic mice that express FRET biosensors. In this study, we report the efficient generation of transgenic mouse lines expressing heritable and functional biosensors for ERK and PKA. These transgenic mice were created by the cytoplasmic co-injection of Tol2 transposase mRNA and a circular plasmid harbouring Tol2 recombination sites. High expression of the biosensors in a wide range of cell types allowed us to screen newborn mice simply by inspection. Observation of these transgenic mice by two-photon excitation microscopy yielded real-time activity maps of ERK and PKA in various tissues, with greatly improved signal-to-background ratios. Our transgenic mice may be bred into diverse genetic backgrounds; moreover, the protocol we have developed paves the way for the generation of transgenic mice that express other FRET biosensors, with important applications in the characterization of physiological and pathological signal transduction events in addition to drug development and screening.

    DOI: 10.1247/csf.11045

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  12. Loss-of-Function Mutation in a Repressor Module of Human-Specifically Activated Enhancer HACNS1 Reviewed

    Kenta Sumiyama, Naruya Saitou

    MOLECULAR BIOLOGY AND EVOLUTION   Vol. 28 ( 11 ) page: 3005 - 3007   2011.11

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:OXFORD UNIV PRESS  

    The cis-regulatory element contributed to gaining humanness is of great interest in human evolutionary studies. A human-accelerated region exceeding neutral evolutionary rates, termed HACNS1, was recently reported as a positively selected sequence acquiring novel TF-binding sites responsible for human-specific gain of limb enhancer function. However, another possibility is loss of function in repressor element in HACNS1. Signature of the human substitutions in the 81-bp region infers that a GC-biased gene conversion (BGC) might create these seemingly excessive substitutions. To evaluate the 81-bp function, we performed transgenic mouse assay of the HACNS1 construct lacking the 81-bp region. The deleted construct showed similar enhancer activity to the intact human HACNS1, suggesting that the function of the human 81-bp region is not an activating enhancer but rather a disrupted repressor. This result infers that loss of function in the HACNS1 81-bp region, possibly via a BGC, played an important role in human-specific evolution.

    DOI: 10.1093/molbev/msr231

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  13. A simple and highly efficient transgenesis method in mice with the Tol2 transposon system and cytoplasmic microinjection Reviewed

    Kenta Sumiyama, Koichi Kawakami, Kazuhiro Yagita

    GENOMICS   Vol. 95 ( 5 ) page: 306 - 311   2010.5

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Creating transgenic mice is an important technology for genetic studies and is currently performed by pronuclear microinjection of plasmid DNA into fertilized eggs. Since survival of injected embryos and integration of plasmid DNA are not efficient, total efficiency is only around 3% with a standard protocol. To circumvent this problem, here we describe a novel transgenesis method, the Tol2-mediated cytoplasmic injection method (Tol2:CI). We injected a foreign DNA cloned in a Tol2-transposon vector together with the transposase mRNA into the cytoplasm of fertilized eggs. As expected, the survival rate of the injected embryos was increased drastically. Also, the foreign DNA was transposed from the plasmid to the genome and transmitted to the next generation very efficiently. Together, the overall transgenic efficiency became more than 20%. Considering its simplicity and perfect compatibility with existing pronuclear microinjection facilities, we propose that the Tol2:CI method is applicable to high throughput functional genomics studies. (C) 2010 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.ygeno.2010.02.006

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  14. Transposon-mediated BAC transgenesis in zebrafish and mice Reviewed

    Maximiliano L. Suster, Kenta Sumiyama, Koichi Kawakami

    BMC GENOMICS   Vol. 10   page: 477   2009.10

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:BIOMED CENTRAL LTD  

    Background: Bacterial artificial chromosomes (BACs) are among the most widely used tools for studies of gene regulation and function in model vertebrates, yet methods for predictable delivery of BAC transgenes to the genome are currently limited. This is because BAC transgenes are usually microinjected as naked DNA into fertilized eggs and are known to integrate as multi-copy concatamers in the genome. Although conventional methods for BAC transgenesis have been very fruitful, complementary methods for generating single copy BAC integrations would be desirable for many applications.
    Results: We took advantage of the precise cut-and-paste behavior of a natural transposon, Tol2, to develop a new method for BAC transgenesis. In this new method, the minimal sequences of the Tol2 transposon were used to deliver precisely single copies of a similar to 70 kb BAC transgene to the zebrafish and mouse genomes. We mapped the BAC insertion sites in the genome by standard PCR methods and confirmed transposase-mediated integrations.
    Conclusion: The Tol2 transposon has a surprisingly large cargo capacity that can be harnessed for BAC transgenesis. The precise delivery of single-copy BAC transgenes by Tol2 represents a useful complement to conventional BAC transgenesis, and could aid greatly in the production of transgenic fish and mice for genomics projects, especially those in which single-copy integrations are desired.

    DOI: 10.1186/1471-2164-10-477

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  15. A cluster of three long-range enhancers directs regional Shh expression in the epithelial linings Reviewed

    Tomoko Sagai, Takanori Amano, Masaru Tamura, Yoichi Mizushina, Kenta Sumiyama, Toshihiko Shiroishi

    DEVELOPMENT   Vol. 136 ( 10 ) page: 1665 - 1674   2009.5

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:COMPANY OF BIOLOGISTS LTD  

    The sonic hedgehog (Shh) pathway plays indispensable roles in the morphogenesis of mouse epithelial linings of the oral cavity and respiratory and digestive tubes. However, no enhancers that regulate regional Shh expression within the epithelial linings have been identified so far. In this study, comparison of genomic sequences across mammalian species and teleost fishes revealed three novel conserved non-coding sequences (CNCSs) that cluster in a region 600 to 900 kb upstream of the transcriptional start site of the mouse Shh gene. These CNCSs drive regional transgenic lacZ reporter expression in the epithelial lining of the oral cavity, pharynx, lung and gut. Together, these enhancers recapitulate the endogenous Shh expression domain within the major epithelial linings. Notably, genomic arrangement of the three CNCSs shows co-linearity that mirrors the order of the epithelial expression domains along the anteroposterior body axis. The results suggest that the three CNCSs are epithelial lining-specific long-range Shh enhancers, and that their actions partition the continuous epithelial linings into three domains: ectoderm-derived oral cavity, endoderm-derived pharynx, and respiratory and digestive tubes of the mouse. Targeted deletion of the pharyngeal epithelium specific CNCS results in loss of endogenous Shh expression in the pharynx and postnatal lethality owing to hypoplasia of the soft palate, epiglottis and arytenoid. Thus, this long-range enhancer is indispensable for morphogenesis of the pharyngeal apparatus.

    DOI: 10.1242/dev.032714

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  16. Possible involvement of SINEs in mammalian-specific brain formation Reviewed

    Takeshi Sasaki, Hidenori Nishihara, Mika Hirakawa, Koji Fujimura, Mikiko Tanaka, Nobuhiro Kokubo, Chiharu Kimura-Yoshida, Isao Matsuo, Kenta Sumiyama, Naruya Saitou, Tomomi Shimogori, Norihiro Okada

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   Vol. 105 ( 11 ) page: 4220 - 4225   2008.3

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:NATL ACAD SCIENCES  

    Retroposons, such as short interspersed elements (SINEs) and long interspersed elements (LINES), are the major constituents of higher vertebrate genomes. Although there are many examples of retroposons&apos; acquiring function, none has been implicated in the morphological innovations specific to a certain taxonomic group. We previously characterized a SINE family, AmnSINE1, members of which constitute a part of conserved noncoding elements (CNEs) in mammalian genomes. We proposed that this family acquired genomic functionality or was exapted after retropositioning in a mammalian ancestor. Here we identified 53 new AmnSINE1 loci and refined 124 total loci, two of which were further analyzed. Using a mouse enhancer assay, we demonstrate that one SINE locus, AS071, 178 kbp from the gene FGF8 (fibroblast growth factor 8), is an enhancer that recapitulates FGF8 expression in two regions of the developing forebrain, namely the diencephalon and the hypothalamus. Our gain-of-function analysis revealed that FGF8 expression in the diencephalon controls patterning of thalamic nuclei, which act as a relay center of the neocortex, suggesting a role for FGF8 in mammalian-specific forebrain patterning. Furthermore, we demonstrated that the locus, AS021, 392 kbp from the gene SATB2, controls gene expression in the lateral telencephalon, which is thought to be a signaling center during development. These results suggest important roles for SINEs in the development of the mammalian neuronal network, a part of which was initiated with the exaptation of AmnSINE1 in a common mammalian ancestor.

    DOI: 10.1073/pnas.0709398105

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  17. Regulation of Dlx3 gene expression in visceral arches by evolutionarily conserved enhancer elements Reviewed

    K Sumiyama, FH Ruddle

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   Vol. 100 ( 7 ) page: 4030 - 4034   2003.4

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    The mammalian Distal-less (Dlx) clusters (Dlx1-2, Dlx5-6, and Dlx3-7) have a nested expression pattern in developing visceral (branchial) arches. Genetic regulatory mechanisms controlling Dlx spatial expression within the visceral arches have not yet been defined. Here we show that an enhancer in the Dlx3-7 cluster can regulate the visceral arch specific expression pattern of the Dlx3 gene. We have used a 79-kb transgene construct containing the entire Dlx3-7 bigene cluster with a LacZ reporter inserted in frame in the first exon of the Dlx3 gene. Visceral arch expression is absent when a 4-kb element located within the Dlx3-7 intergenic region is deleted. A 245-by element (137-2) whose DNA sequence is highly conserved between human and mouse located within the 4kb-deleted region can drive visceral arch expression when fused to a hsp68-lacZ reporter transgene construct. Reporter expression is detected in 9.5 and 10.5 days postcoitum transgenic embryos in a manner consistent with the endogenous Dlx3 expression pattern in the mesenchyme of the first and second visceral arches. Thus the 137-2 element is both necessary and sufficient for Dlx3 expression. The 137-2 element contains several putative binding sites for several transcription factors including Dlx and other homeodomain proteins within the evolutionarily conserved region. Significantly, the 137-2 element shows a sequence-match including a Dlx binding site to a cis-element in the Dlx5-6 intermediate region designated ml56i [Zerucha, T., Stuhmer, T., Hatch, G., Park, B. K., Long, Q., Yu, G., Gambarotta, A., Schultz, J. R., Rubenstein, J. L. & Ekker, M. (2000) J.. Neurosci. 20, 709-721], despite distant phylogenetic relationship between these clusters. Our results provide evidence for a concerted role for DLX auto- and cross-regulation in the establishment of a nested expression pattern for Dlx3-7 and Dlx5-6 clusters within the visceral arches.

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  18. The role of gene duplication in the evolution and function of the vertebrate Dlx/distal-less bigene clusters. Reviewed

    Sumiyama K, Irvine SQ, Ruddle FH

    Journal of structural and functional genomics   Vol. 3   page: 151 - 159   2003

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  19. Adaptive evolution of the IgA hinge region in primates Reviewed

    K Sumiyama, N Saitou, S Ueda

    MOLECULAR BIOLOGY AND EVOLUTION   Vol. 19 ( 7 ) page: 1093 - 1099   2002.7

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    IgA is a major component that prevents the penetration of pathogenic bacteria into mucosal Surfaces. The I-A antibody is cleaved at the IgA hinge region with high specificity by IgA-specific proteases produced by several pathogenic bacteria. We conducted a genomic sequence analysis of the IgA genes of a wide spectrum of primates, including the first intron and second exon, which consist of the hinge region and the CH2 domain, to find evidence of positive selection. Because the hinge region is quite small, we combined the largest collection of sequences that could be clearly aligned and evaluated the total numbers of synonymous and nonsynonymous substitutions on the phylogenctic tree. The nonsynonymous to synonymous substitution ratio (d(N)/d(S) test) showed that hominoids, Old World monkeys, and New World monkeys have d(N)/d(S) ratios of 5.4, 6.3, and 4.2, respectively. Fisher's exact probability tests showed statistical significance for the Old World monkey. Because the substitution rates of the flanking sequences are more or less similar to the synonymous rates of the hinge region, these high values of d(N)/d(S) should be the result of positive selection at the hinge region. Combining the high sequence variability in each population and the highly accelerated nonsynonymous substitution rates in the hinge region, we conclude that this unusual IgA evolution is a molecular evidence of adaptive evolution possibly caused by the host-parasite relationship.

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  20. Genomic structure and functional control of the Dlx3-7 bigene cluster Reviewed

    K Sumiyama, SQ Irvine, DW Stock, KM Weiss, K Kawasaki, N Shimizu, CS Shashikant, W Miller, FH Ruddle

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   Vol. 99 ( 2 ) page: 780 - 785   2002.1

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    The Dlx genes are involved in early vertebrate morphogenesis, notably of the head. The six Dlx genes of mammals are arranged in three convergently transcribed bigene clusters. In this study, we examine the regulation of the Dlx3-7 cluster of the mouse. We obtained and sequenced human and mouse P1 clones covering the entire Dlx3-7 cluster. Comparative analysis of the human and mouse sequences revealed several highly conserved noncoding regions within 30 kb of the Dlx3-7-coding regions. These conserved elements were located both 5' of the coding exons of each gene and in the intergenic region 3' of the exons, suggesting that some enhancers might be shared between genes. We also found that the protein sequence of Dlx7 is evolving more rapidly than that of Dlx3. We conducted a functional study of the 79-kb mouse genomic clone to locate cis-element activity able to reproduce the endogenous expression pattern by using transgenic mice. We inserted a lacZ reporter gene into the first exon of the Dlx3 gene by using homologous recombination in yeast. Strong lacZ expression in embryonic (E) stage E9.5 and E10.5 mouse embryos was found in the limb buds and first and second visceral arches, consistent with the endogenous Dlx3 expression pattern. This result shows that the 79-kb region contains the major cis-elements required to direct the endogenous expression of Dlx3 at stage E10.5. To test for enhancer location, we divided the construct in the mid-intergenic region and injected the Dlx3 gene portion. This shortened fragment lacking Dlx7-flanking sequences is able to drive expression in the limb buds but not in the visceral arches. This observation is consistent with a cis-regulatory enhancer-sharing model within the Dlx bigene cluster.

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  21. An efficient cis-element discovery method using multiple sequence comparisons based on evolutionary relationships Reviewed

    K Sumiyama, CB Kim, FH Ruddle

    GENOMICS   Vol. 71 ( 2 ) page: 260 - 262   2001.1

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    The discovery of cis-element control motifs in noncoding DNA poses a difficult problem in genome analysis. Functional analysis by means of reporter constructs expressed in transgenic organisms is the most reliable method, but is by itself time-consuming and expensive, Searching noncoding DNA for known control motifs by sequence analysis is problematic, since protein binding motifs are short, in the range of 8-10 bp, and occur frequently by chance. Heretofore, the most reliable sequence analysis method has been the comparison of homologous sequence domains in related but moderately evolutionarily divergent species such as, for example, mouse and human. In such pairwise combinations, control regions are conserved because they serve a vital function and can be identified by their similar sequences, Single pairwise comparisons, however, allow the discovery of conserved sequence strings only at low resolution and without specific identity. We have investigated the possibility of using multiple sequence comparisons to correct these shortcomings. We applied this method to the Hoxc8 early enhancer region that has been previously analyzed in depth by functional methods and through its application successfully identified known protein binding cis-element motifs, candidate protein binding sites could also be identified. This method, based on evolutionarily related sequence comparisons, should be quite useful as a prescreening step prior to functional analysis with corresponding savings in time and resources. (C) 2001 Academic Press.

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  22. Class III POU genes: Generation of homopolymeric amino acid repeats under GC pressure in mammals Reviewed

    K Sumiyama, K WashioWatanabe, N Saitou, T Hayakawa, S Ueda

    JOURNAL OF MOLECULAR EVOLUTION   Vol. 43 ( 3 ) page: 170 - 178   1996.9

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    The class III POU transcription factor genes play an important role in the nervous system. Comparison of their entire amino acid sequences disclosed a remarkable feature of particular mammalian class III POU genes. Alanine, glycine, and proline repeats were present in the mammalian Brain-1 gene, whereas most of these repeats were absent in the nonmammalian homologue. The mammalian Brain-2 gene had alanine, glycine, proline, and glutamine repeats, which were missing in the nonmammalian homologue. The mammalian Scip gene had alanine, glycine, proline, and histidine repeats, but the nonmammalian homologue completely lacked these repeats. In contrast, the mammalian Brain-4 gene had no amino acid repeats like its nonmammalian homologue. The mammalian genes containing the characteristic amino acid repeats had another feature, higher GC content. We found a positive correlation between the GC content and the amino acid repeat ratio. Those amino acids were encoded by triplet codons with relatively high GC content. These results suggest that the GC pressure has facilitated generation of the homopolymeric amino acid repeats.

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  23. Circadian ribosome profiling reveals a role for the <i>Period2</i> upstream opening reading frame in sleep

    Arthur Millius, Rikuhiro Yamada, Hiroshi Fujishima, Kazuhiko Maeda, Daron M. Standley, Kenta Sumiyama, Dimitri Perrin, Hiroki R. Ueda

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    Many mammalian proteins have circadian cycles of production and degradation, but de novo transcription is only responsible for a small fraction of this rhythmicity. We used ribosome profiling to quantify RNA translation in liver from circadian-entrained mice transferred to constant darkness conditions over a 24-h period and compared translation levels to absolute protein production for 16 circadian proteins. We observed a delay between translation and peak protein levels for several circadian genes covering a wide range of translation efficiencies. We found extensive binding of ribosomes to upstream open reading frames (uORFs) in circadian mRNAs, including the core clock gene Period2 (Per2). Increased uORFs in 5’ UTRs was associated with decreased ribosome binding in downstream ORFs and reduced expression of synthetic reporter constructs in vitro and in single cells. Mutation of the Per2 uORF increased luciferase and fluorescence reporter expression in 3T3 cells without altering phase or period. Genomic Per2 uORF mutation using CRISPR/Cas9 increased PER2 expression in PER2:Luc MEFs and reduced sleep in Per2 uORF mutant mice. These results suggest that post-transcriptional processes shape translation of mRNA transcripts, which can impact physiological rhythms and sleep.

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  24. A FRET biosensor, SMART, monitors necroptosis in renal tubular epithelial cells in a cisplatin-induced kidney injury model

    Shin Murai, Kanako Takakura, Kenta Sumiyama, Kenta Moriwaki, Kenta Terai, Sachiko Komazawa-Sakon, Yoshifumi Yamaguchi, Tetuo Mikami, Kimi Araki, Masaki Ohmuraya, Michiyuki Matsuda, Hiroyasu Nakano

        2022.6

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    Necroptosis is a regulated form of cell death involved in various pathological conditions, including ischemic reperfusion injuries, virus infections, and drug-induced tissue injuries. However, it is not fully understood when and where necroptosis occurs in vivo. We previously generated a Forster resonance energy transfer (FRET) biosensor, termed SMART (the sensor for MLKL activation based on FRET), which specifically monitored necroptosis in human and murine cell lines in vitro. Here, we generated transgenic (Tg) mice that expressed the SMART biosensor in various tissues. SMART monitored necroptosis, but not apoptosis or pyroptosis, in primary cells, including peritoneal macrophages and embryonic fibroblasts. Moreover, the FRET signal was elevated in renal tubular cells of cisplatin-treated SMART Tg mice compared to untreated SMART Tg mice. Together, SMART Tg mice may provide a valuable tool for monitoring necroptosis in different types of cells in vitro and in vivo.

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  25. Functional visualization of NK Cell-mediated killing of metastatic single tumor cells. International journal

    Hiroshi Ichise, Shoko Tsukamoto, Tsuyoshi Hirashima, Yoshinobu Konishi, Choji Oki, Shinya Tsukiji, Satoshi Iwano, Atsushi Miyawaki, Kenta Sumiyama, Kenta Terai, Michiyuki Matsuda

    eLife   Vol. 11   2022.2

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    Natural killer (NK) cells lyse invading tumor cells to limit metastatic growth in the lung, but how some cancers evade this host protective mechanism to establish a growing lesion is unknown. Here we have combined ultra-sensitive bioluminescence imaging with intravital two-photon microscopy involving genetically-encoded biosensors to examine this question. NK cells eliminated disseminated tumor cells from the lung within 24 hrs of arrival, but not thereafter. Intravital dynamic imaging revealed that 50% of NK-tumor cell encounters lead to tumor cell death in the first 4 hrs after tumor cell arrival, but after 24 hrs of arrival, nearly 100% of the interactions result in the survival of the tumor cell. During this 24 hrs period, the probability of ERK activation in NK cells upon encountering the tumor cells was decreased from 68% to 8%, which correlated with the loss of the activating ligand CD155/PVR/Necl5 from the tumor cell surface. Thus, by quantitatively visualizing the NK-tumor cell interaction at the early stage of metastasis, we have revealed the crucial parameters of NK cell immune surveillance in the lung.

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  26. Two-photon AMPK and ATP imaging reveals the bias between rods and cones in glycolysis utility. Reviewed International journal

    Jiazhou He, Masamichi Yamamoto, Kenta Sumiyama, Yumi Konagaya, Kenta Terai, Michiyuki Matsuda, Shinya Sato

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology   Vol. 35 ( 9 ) page: e21880   2021.9

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    In vertebrates, retinal rod and cone photoreceptor cells rely significantly on glycolysis. Lactate released from photoreceptor cells fuels neighboring retinal pigment epithelium cells and Müller glial cells through oxidative phosphorylation. To understand this highly heterogeneous metabolic environment around photoreceptor cells, single-cell analysis is needed. Here, we visualized cellular AMP-activated protein kinase (AMPK) activity and ATP levels in the retina by two-photon microscopy. Transgenic mice expressing a hyBRET-AMPK biosensor were used for measuring the AMPK activity. GO-ATeam2 transgenic mice were used for measuring the ATP level. Temporal metabolic responses were successfully detected in the live retinal explants upon drug perfusion. A glycolysis inhibitor, 2-deoxy-d-glucose (2-DG), activated AMPK and reduced ATP. These effects were clearly stronger in rods than in cones. Notably, rod AMPK and ATP started to recover at 30 min from the onset of 2-DG perfusion. Consistent with these findings, ex vivo electroretinogram recordings showed a transient slowdown in rod dim flash responses during a 60-min 2-DG perfusion, whereas cone responses were not affected. Based on these results, we propose that cones surrounded by highly glycolytic rods become less dependent on glycolysis, and rods also become less dependent on glycolysis within 60 min upon the glycolysis inhibition.

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  27. A human isogenic iPSC-derived cell line panel identifies major regulators of aberrant astrocyte proliferation in Down syndrome. Reviewed International journal

    Keiji Kawatani, Toshihiko Nambara, Nobutoshi Nawa, Hidetaka Yoshimatsu, Haruna Kusakabe, Katsuya Hirata, Akira Tanave, Kenta Sumiyama, Kimihiko Banno, Hidetoshi Taniguchi, Hitomi Arahori, Keiichi Ozono, Yasuji Kitabatake

    Communications biology   Vol. 4 ( 1 ) page: 730 - 730   2021.6

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    Astrocytes exert adverse effects on the brains of individuals with Down syndrome (DS). Although a neurogenic-to-gliogenic shift in the fate-specification step has been reported, the mechanisms and key regulators underlying the accelerated proliferation of astrocyte precursor cells (APCs) in DS remain elusive. Here, we established a human isogenic cell line panel based on DS-specific induced pluripotent stem cells, the XIST-mediated transcriptional silencing system in trisomic chromosome 21, and genome/chromosome-editing technologies to eliminate phenotypic fluctuations caused by genetic variation. The transcriptional responses of genes observed upon XIST induction and/or downregulation are not uniform, and only a small subset of genes show a characteristic expression pattern, which is consistent with the proliferative phenotypes of DS APCs. Comparative analysis and experimental verification using gene modification reveal dose-dependent proliferation-promoting activity of DYRK1A and PIGP on DS APCs. Our collection of human isogenic cell lines provides a comprehensive set of cellular models for further DS investigations.

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  28. Metastatic Single Tumor Cells Evade NK Cell-mediated Killing by Thrombin-mediated Loss of the Activating Ligand CD155/PVR/Necl-5

    Hiroshi Ichise, Shoko Tsukamoto, Tsuyoshi Hirashima, Yoshinobu Konishi, Choji Oki, Shinya Tsukiji, Satoshi Iwano, Atsushi Miyawaki, Kenta Sumiyama, Kenta Terai, Michiyuki Matsuda

        2021.1

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    <title>ABSTRACT</title>Natural killer (NK) cells lyse invading tumor cells to limit metastatic growth in the lung, but how some cancers evade this host protective mechanism to establish a growing lesion is not known. Here we have combined ultra-sensitive bioluminescence whole body imaging with intravital two-photon microscopy involving genetically-encoded biosensors to examine this question. NK cells eliminated disseminated tumor cells from the lung within 24 hrs of arrival, but not thereafter. Intravital dynamic imaging revealed that a disseminated tumor cell in a pulmonary capillary interacts with an NK cell every 2 hrs on average. In the first 4 hrs after tumor cell arrival, 50% of such encounters lead to tumor cell death but after 24 hrs of arrival, nearly 100% of the interactions result in the survival of the tumor cell. This evasion of NK cell surveillance is mediated by thrombin-dependent loss of cell surface CD155/PVR/Necl-5, a ligand for the NK cell activating receptor DNAM-1. This loss prevents the NK cell signaling needed for effective killing of tumor targets. By quantitatively visualizing the evasion of NK cell surveillance, we have uncovered a molecular mechanism for cancer evasion and provided an explanation for the anti-metastatic effect of anticoagulants.

    <sec><title>SUMMARY</title>Intravital functional two-photon microscopy reveals that metastatic tumor cells lodged in pulmonary capillaries acquire resistance to patrolling NK cells. Protease-mediated loss of the activating ligand CD155/PVR/Necl-5 on tumor cells prevents NK cells from ERK activation and tumor cell killing.

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  29. Visualization of Spatially Controlled Vasospasm by Sympathetic Nerve-Mediated ROCK Activation. Reviewed International journal

    Ayako Imanishi, Hiroshi Ichise, Chuyun Fan, Yasuaki Nakagawa, Koichiro Kuwahara, Kenta Sumiyama, Michiyuki Matsuda, Kenta Terai

    The American journal of pathology   Vol. 191 ( 1 ) page: 194 - 203   2020.10

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    Contraction of vascular smooth muscle is regulated primarily by calcium concentration and secondarily by ROCK activity within the cells. In contrast to the regulation of calcium concentration, little is known about the spatio-temporal regulation of ROCK activity in live blood vessels. Here, we report ROCK activation in subcutaneous arterioles in a transgenic mouse line, which expresses a genetically-encoded ROCK biosensor based on the principle of Fӧrster resonance energy transfer by two-photon excitation in vivo imaging. Upon laser ablation of arterioles, rapid vasospasm was induced, concomitant with a transient increase in calcium concentration in arteriolar smooth muscles. Unlike the increase in calcium concentration, vasoconstriction and ROCK activation continued for several minutes. Both the ROCK inhibitor, fasudil, and the ganglionic nicotinic acetylcholine receptor blocker, hexamethonium, inhibited laser-induced ROCK activation and reduced the duration of vasospasm at the segments distant from the irradiated point. These observations suggest that vasoconstriction is initially triggered by a rapid surge of cytoplasmic calcium concentration and then maintained by sympathetic nerve-mediated ROCK activation.

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  30. Gsx2 is required for specification of neurons in the inferior olivary nuclei from Ptf1a-expressing neural progenitors in zebrafish. Reviewed International journal

    Tsubasa Itoh, Miki Takeuchi, Marina Sakagami, Kazuhide Asakawa, Kenta Sumiyama, Koichi Kawakami, Takashi Shimizu, Masahiko Hibi

    Development (Cambridge, England)   Vol. 147 ( 19 )   2020.10

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    Neurons in the inferior olivary nuclei (IO neurons) send climbing fibers to Purkinje cells to elicit functions of the cerebellum. IO neurons and Purkinje cells are derived from neural progenitors expressing the proneural gene ptf1a In this study, we found that the homeobox gene gsx2 was co-expressed with ptf1a in IO progenitors in zebrafish. Both gsx2 and ptf1a zebrafish mutants showed a strong reduction or loss of IO neurons. The expression of ptf1a was not affected in gsx2 mutants, and vice versa. In IO progenitors, the ptf1a mutation increased apoptosis whereas the gsx2 mutation did not, suggesting that ptf1a and gsx2 are regulated independently of each other and have distinct roles. The fibroblast growth factors (Fgf) 3 and 8a, and retinoic acid signals negatively and positively, respectively, regulated gsx2 expression and thereby the development of IO neurons. mafba and Hox genes are at least partly involved in the Fgf- and retinoic acid-dependent regulation of IO neuronal development. Our results indicate that gsx2 mediates the rostro-caudal positional signals to specify the identity of IO neurons from ptf1a-expressing neural progenitors.

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  31. Biliverdin Reductase-A Deficiency Brighten and Sensitize Biliverdin-binding Chromoproteins. Reviewed

    Kenju Kobachi, Sota Kuno, Shinya Sato, Kenta Sumiyama, Michiyuki Matsuda, Kenta Terai

    Cell structure and function   Vol. 45 ( 2 ) page: 131 - 141   2020.8

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    Tissue absorbance, light scattering, and autofluorescence are significantly lower in the near-infrared (NIR) range than in the visible range. Because of these advantages, NIR fluorescent proteins (FPs) are in high demand for in vivo imaging. Nevertheless, application of NIR FPs such as iRFP is still limited due to their dimness in mammalian cells. In contrast to GFP and its variants, iRFP requires biliverdin (BV) as a chromophore. The dimness of iRFP is at least partly due to rapid reduction of BV by biliverdin reductase-A (BLVRA). Here, we established biliverdin reductase-a knockout (Blvra-/-) mice to increase the intracellular BV concentration and, thereby, to enhance iRFP fluorescence intensity. As anticipated, iRFP fluorescence intensity was significantly increased in all examined tissues of Blvra-/- mice. Similarly, the genetically encoded calcium indicator NIR-GECO1, which is engineered based on another NIR FP, mIFP, exhibited a marked increase in fluorescence intensity in mouse embryonic fibroblasts derived from Blvra-/- mice. We expanded this approach to an NIR light-sensing optogenetic tool, the BphP1-PpsR2 system, which also requires BV as a chromophore. Again, deletion of the Blvra gene markedly enhanced the light response in HeLa cells. These results indicate that the Blvra-/- mouse is a versatile tool for the in vivo application of NIR FPs and NIR light-sensing optogenetic tools.Key words: in vivo imaging, near-infrared fluorescent protein, biliverdin, biliverdin reductase, optogenetic tool.

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  32. Booster, a Red-Shifted Genetically Encoded Förster Resonance Energy Transfer (FRET) Biosensor Compatible with Cyan Fluorescent Protein/Yellow Fluorescent Protein-Based FRET Biosensors and Blue Light-Responsive Optogenetic Tools. Reviewed International journal

    Tetsuya Watabe, Kenta Terai, Kenta Sumiyama, Michiyuki Matsuda

    ACS sensors   Vol. 5 ( 3 ) page: 719 - 730   2020.3

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    Genetically encoded Förster resonance energy transfer (FRET)-based biosensors have been developed for the visualization of signaling molecule activities. Currently, most of them are comprised of cyan and yellow fluorescent proteins (CFP and YFP), precluding the use of multiple FRET biosensors within a single cell. Moreover, the FRET biosensors based on CFP and YFP are incompatible with the optogenetic tools that operate at blue light. To overcome these problems, here, we have developed FRET biosensors with red-shifted excitation and emission wavelengths. We chose mKOκ and mKate2 as the favorable donor and acceptor pair by calculating the Förster distance. By optimizing the order of fluorescent proteins and modulatory domains of the FRET biosensors, we developed a FRET biosensor backbone named "Booster". The performance of the protein kinase A (PKA) biosensor based on the Booster backbone (Booster-PKA) was comparable to that of AKAR3EV, a previously developed FRET biosensor comprising CFP and YFP. For the proof of concept, we first showed simultaneous monitoring of activities of two protein kinases with Booster-PKA and ERK FRET biosensors based on CFP and YFP. Second, we showed monitoring of PKA activation by Beggiatoa photoactivated adenylyl cyclase, an optogenetic generator of cyclic AMP. Finally, we presented PKA activity in living tissues of transgenic mice expressing Booster-PKA. Collectively, the results demonstrate the effectiveness and versatility of Booster biosensors as an imaging tool in vitro and in vivo.

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  33. Mark1 regulates distal airspace expansion through type I pneumocyte flattening in lung development. Reviewed International journal

    Katsumi Fumoto, Hisako Takigawa-Imamura, Kenta Sumiyama, Shige H Yoshimura, Natsumi Maehara, Akira Kikuchi

    Journal of cell science   Vol. 132 ( 24 )   2019.12

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    During the later stages of lung development, two types of pneumocytes, cuboidal type II (AECII) and flattened type I (AECI) alveolar epithelial cells, form distal lung saccules. Here, we highlight how fibroblasts expressing MAP-microtubule affinity regulating kinase 1 (Mark1) are required for the terminal stages of pulmonary development, called lung sacculation. In Mark1-knockout (KO) mice, distal sacculation and AECI flattening are significantly impaired. Fetal epithelial cells generate alveolar organoids and differentiate into pneumocytes when co-cultured with fibroblasts. However, the size of organoids decreased and AECI flattening was impaired in the presence of Mark1 KO fibroblasts. In Mark1 KO fibroblasts themselves, cilia formation and the Hedgehog pathway were suppressed, resulting in the loss of type I collagen expression. The addition of type I collagen restored AECI flattening in organoids co-cultured with Mark1 KO fibroblasts and rescued the decreased size of organoids. Mathematical modeling of distal lung sacculation supports the view that AECI flattening is necessary for the proper formation of saccule-like structures. These results suggest that Mark1-mediated fibroblast activation induces AECI flattening and thereby regulates distal lung sacculation.

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  34. 細胞・組織動態解析と数理モデルで解く形態形成の原理 オルガノイドと数理モデルで迫る形態形成の仕組み

    麓 勝己, 今村 寿子, 隅山 健太, 吉村 成弘, 菊池 章

    日本生化学会大会プログラム・講演要旨集   Vol. 92回   page: [2S15a - 04]   2019.9

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  35. Expression of plasma membrane calcium ATPases confers Ca2+/H+ exchange in rodent synaptic vesicles. Reviewed International journal

    Yoshiyasu Ono, Yasunori Mori, Yoshihiro Egashira, Kenta Sumiyama, Shigeo Takamori

    Scientific reports   Vol. 9 ( 1 ) page: 4289 - 4289   2019.3

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    Ca2+ transport into synaptic vesicles (SVs) at the presynaptic terminals has been proposed to be an important process for regulating presynaptic [Ca2+] during stimulation as well as at rest. However, the molecular identity of the transport system remains elusive. Previous studies have demonstrated that isolated SVs exhibit two distinct Ca2+ transport systems depending on extra-vesicular (cytosolic) pH; one is mediated by a high affinity Ca2+ transporter which is active at neutral pH and the other is mediated by a low affinity Ca2+/H+ antiporter which is maximally active at alkaline pH of 8.5. In addition, synaptic vesicle glycoprotein 2 s (SV2s), a major SV component, have been proposed to contribute to Ca2+ clearance from the presynaptic cytoplasm. Here, we show that at physiological pH, the plasma membrane Ca2+ ATPases (PMCAs) are responsible for both the Ca2+/H+ exchange activity and Ca2+ uptake into SVs. The Ca2+/H+ exchange activity monitored by acidification assay exhibited high affinity for Ca2+ (Km ~ 400 nM) and characteristic divalent cation selectivity for the PMCAs. Both activities were remarkably reduced by PMCA blockers, but not by a blocker of the ATPase that transfers Ca2+ from the cytosol to the lumen of sarcoplasmic endoplasmic reticulum (SERCA) at physiological pH. Furthermore, we rule out the contribution of SV2s, putative Ca2+ transporters on SVs, since both Ca2+/H+ exchange activity and Ca2+ transport were unaffected in isolated vesicles derived from SV2-deficient brains. Finally, using a PMCA1-pHluorin construct that enabled us to monitor cellular distribution and recycling properties in living neurons, we demonstrated that PMCA1-pHluorin localized to intracellular acidic compartments and recycled at presynaptic terminals in an activity-dependent manner. Collectively, our results imply that vesicular PMCAs may play pivotal roles in both presynaptic Ca2+ homeostasis and the modulation of H+ gradient in SVs.

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  36. Composite regulation of ERK activity dynamics underlying tumour-specific traits in the intestine Reviewed

    Yu Muta, Yoshihisa Fujita, Kenta Sumiyama, Atsuro Sakurai, M. Mark Taketo, Tsutomu Chiba, Hiroshi Seno, Kazuhiro Aoki, Michiyuki Matsuda, Masamichi Imajo

    Nature Communications   Vol. 9 ( 1 ) page: 2174   2018.12

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    Acting downstream of many growth factors, extracellular signal-regulated kinase (ERK) plays a pivotal role in regulating cell proliferation and tumorigenesis, where its spatiotemporal dynamics, as well as its strength, determine cellular responses. Here, we uncover the ERK activity dynamics in intestinal epithelial cells (IECs) and their association with tumour characteristics. Intravital imaging identifies two distinct modes of ERK activity, sustained and pulse-like activity, in IECs. The sustained and pulse-like activities depend on ErbB2 and EGFR, respectively. Notably, activation of Wnt signalling, the earliest event in intestinal tumorigenesis, augments EGFR signalling and increases the frequency of ERK activity pulses through controlling the expression of EGFR and its regulators, rendering IECs sensitive to EGFR inhibition. Furthermore, the increased pulse frequency is correlated with increased cell proliferation. Thus, ERK activity dynamics are defined by composite inputs from EGFR and ErbB2 signalling in IECs and their alterations might underlie tumour-specific sensitivity to pharmacological EGFR inhibition.

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  37. A platform of BRET-FRET hybrid biosensors for optogenetics, chemical screening, and in vivo imaging. Reviewed International journal

    Naoki Komatsu, Kenta Terai, Ayako Imanishi, Yuji Kamioka, Kenta Sumiyama, Takashi Jin, Yasushi Okada, Takeharu Nagai, Michiyuki Matsuda

    Scientific reports   Vol. 8 ( 1 ) page: 8984 - 8984   2018.6

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    Genetically encoded biosensors based on the principle of Förster resonance energy transfer comprise two major classes: biosensors based on fluorescence resonance energy transfer (FRET) and those based on bioluminescence energy transfer (BRET). The FRET biosensors visualize signaling-molecule activity in cells or tissues with high resolution. Meanwhile, due to the low background signal, the BRET biosensors are primarily used in drug screening. Here, we report a protocol to transform intramolecular FRET biosensors to BRET-FRET hybrid biosensors called hyBRET biosensors. The hyBRET biosensors retain all properties of the prototype FRET biosensors and also work as BRET biosensors with dynamic ranges comparable to the prototype FRET biosensors. The hyBRET biosensors are compatible with optogenetics, luminescence microplate reader assays, and non-invasive whole-body imaging of xenograft and transgenic mice. This simple protocol will expand the use of FRET biosensors and enable visualization of the multiscale dynamics of cell signaling in live animals.

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  38. Oocyte all-surfaces’ imaging method using micro-scale rotational flow Reviewed

    Yaxiaer Yalikun, Yusufu Aishan, Abulaiti Mosha, Kenta Sumiyama, Yo Tanaka

    Micro and Nano Letters   Vol. 13 ( 3 ) page: 306 - 311   2018.3

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    In this work, the authors report an all-surfaces’ image capturing method of a single oocyte that uses micro-scale rotational flow. Here, the authors used this method gently and indirectly rotated the single pronuclear zygotes (physical properties are similar to those of oocytes) to obtain images of all its surfaces in 0.33 s. The necessary equipment to realise this method consists of only a syringe pump and a microfluidic chip with a single 40 µm diameter orifice. Assessment of viability and quality of oocytes or embryos during the process of intra cytoplasmic sperm injection) and in vitro fertilisation is important for good embryo development. At present, manual morphological evaluation is the most common method to assess viability and quality of oocytes. Usually, during the manual morphological evaluation, the operator is required to manipulate the oocyte to achieve its full surface image. However, manipulation is difficult, even for an experienced operator. Conventional methods using the principles of mechanics, electronics, or magnetism require a complex system. Conventional methods using principles of fluids or optics also have limitations about target size and transparency. Here, a method is proposed and proved of using rotational flow to gently capture and rotate a mouse zygote without using a complex control system and achieved its full surface image in 0.33 s. The method offers a new tool for morphological evaluation of assessment of viability and quality of oocytes.

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  39. A Highly Sensitive FRET Biosensor for AMPK Exhibits Heterogeneous AMPK Responses among Cells and Organs Reviewed

    Yumi Konagaya, Kenta Terai, Yusuke Hirao, Kanako Takakura, Masamichi Imajo, Yuji Kamioka, Norio Sasaoka, Akira Kakizuka, Kenta Sumiyama, Tomoichiro Asano, Michiyuki Matsuda

    CELL REPORTS   Vol. 21 ( 9 ) page: 2628 - 2638   2017.11

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    AMP-activated protein kinase (AMPK), a master regulator of cellular metabolism, is a potential target for type 2 diabetes. Although extensive in vitro studies have revealed the complex regulation of AMPK, much remains unknown about the regulation in vivo. We therefore developed transgenic mice expressing a highly sensitive fluorescence resonance energy transfer (FRET)-based biosensor for AMPK, called AMPKAR-EV. AMPKAR-EV allowed us to readily examine the role of LKB1, a canonical stimulator of AMPK, in drug-induced activation and inactivation of AMPK in vitro. In transgenic mice expressing AMPKAR-EV, the AMP analog AICAR activated AMPK in muscle. In contrast, the antidiabetic drug metformin activated AMPK in liver, highlighting the organ-specific action of AMPK stimulators. Moreover, we found that AMPK was activated primarily in fast-twitch muscle fibers after tetanic contraction and exercise. These observations suggest that the AMPKAR-EV mouse will pave a way to understanding the heterogeneous responses of AMPK among cell types in vivo.

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  40. All surface imaging method of oocyte by using smaller vertical rotational flow Reviewed

    Y. Yalikun, Y.Aishan, K.Sumiyama, Y.Tanaka

    Proceeding of International Conference on Miniaturized Systems for Chemistry and Life Sciences (MicroTAS 2017)     2017.11

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  41. Live imaging of extracellular signal-regulated kinase and protein kinase A activities during thrombus formation in mice expressing biosensors based on Forster resonance energy transfer Reviewed

    T. Hiratsuka, T. Sano, H. Kato, N. Komatsu, M. Imajo, Y. Kamioka, K. Sumiyama, F. Banno, T. Miyata, M. Matsuda

    JOURNAL OF THROMBOSIS AND HAEMOSTASIS   Vol. 15 ( 7 ) page: 1487 - 1499   2017.7

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    Background: The dynamic features of thrombus formation have been visualized by conventional video widefield microscopy or confocal microscopy in live mice. However, owing to technical limitations, the precise spatiotemporal regulation of intracellular signaling molecule activities, which have been extensively studied in vitro, remains elusive in vivo. Objectives: To visualize, by the use of two-photon excitation microscopy of transgenic mice expressing Forster resonance energy transfer (FRET) biosensors for extracellular signal-regulated kinase (ERK) and protein kinase A (PKA), ERK and PKA activities during thrombus formation in laser-injured subcutaneous arterioles. Results: When a core of densely packed platelets had developed, ERK activity was increased from the basal region close to the injured arterioles. PKA was activated at the downstream side of an unstable shell overlaying the core of platelets. Intravenous administration of a MEK inhibitor, PD0325901, suppressed platelet tethering and dislodged platelet aggregates, indicating that ERK activity is indispensable for both initiation and maintenance of the thrombus. A cAMP analog, dbcAMP, inhibited platelet tethering but failed to dislodge the preformed platelet aggregates, suggesting that PKA can antagonize thrombus formation only in the early phase. Conclusion: In vivo imaging of transgenic mice expressing FRET biosensors will open a new opportunity to visualize the spatiotemporal changes in signaling molecule activities not only during thrombus formation but also in other hematologic disorders.

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  42. Intravital Forster resonance energy transfer imaging reveals osteopontin-mediated polymorphonuclear leukocyte activation by tumor cell emboli Reviewed

    Yuji Kamioka, Kanako Takakura, Kenta Sumiyama, Michiyuki Matsuda

    CANCER SCIENCE   Vol. 108 ( 2 ) page: 226 - 235   2017.2

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    Myeloid-derived suppressor cells (MDSCs) cause paraneoplastic leukemoid reactions and facilitate tumor cell metastasis. However, the interaction of MDSCs with tumor cells in live tissue has not been adequately visualized. To accomplish this task, we developed an intravital imaging protocol to observe metastasized tumor cells in mouse lungs. For visualization of the activation of MDSCs, bone marrow cells derived from transgenic mice expressing a Forster resonance energy transfer biosensor for ERK were implanted into host mice. Under a two-photon excitation microscope, numerous polymorphonuclear cells (PMNs) were found to infiltrate the lungs of tumor-bearing mice in which 4T1 mammary tumor cells were implanted into the footpads. By Forster resonance energy transfer imaging, we found ERK activation in PMNs around the 4T1 tumor emboli in the lungs. Because antibody array analysis implied the involvement of osteopontin (OPN) in the metastasis of 4T1 cells, we further analyzed the effect of OPN knockdown. The OPN knockdown in 4T1 cells did not affect the cell growth, but markedly suppressed lung metastasis of 4T1 cells and ERK activation in PMNs in the lung. Intravenous injection of recombinant OPN restored the lung metastasis of OPN-deficient 4T1 cells, suggesting that OPN functioned in a paracrine manner. It has been reported that ERK activation of neutrophils causes NETosis and that PMNs promote metastasis of tumor cells by NETosis. In agreement with previous reports, the NETosis inhibitor DNase I inhibited lung metastasis of 4T1 cells. These observations suggest that OPN promotes metastasis of 4T1 cells by activating PMNs and inducing NETosis.

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  43. Modulation of apical constriction by Wnt signaling is required for lung epithelial shape transition Reviewed

    Katsumi Fumoto, Hisako Takigawa-Imamura, Kenta Sumiyama, Tomoyuki Kaneiwa, Akira Kikuchi

    DEVELOPMENT   Vol. 144 ( 1 ) page: 151 - 162   2017.1

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    In lung development, the apically constricted columnar epithelium forms numerous buds during the pseudoglandular stage. Subsequently, these epithelial cells change shape into the flat or cuboidal pneumocytes that form the air sacs during the canalicular and saccular (canalicular-saccular) stages, yet the impact of cell shape on tissue morphogenesis remains unclear. Here, we show that the expression of Wnt components is decreased in the canalicular-saccular stages, and that genetically constitutive activation of Wnt signaling impairs air sac formation by inducing apical constriction in the epithelium as seen in the pseudoglandular stage. Organ culture models also demonstrate that Wnt signaling induces apical constriction through apical actomyosin cytoskeletal organization. Mathematical modeling reveals that apical constriction induces bud formation and that loss of apical constriction is required for the formation of an air sac-like structure. We identify MAP/microtubule affinity-regulating kinase 1 (Mark1) as a downstream molecule of Wnt signaling and show that it is required for apical cytoskeletal organization and bud formation. These results suggest that Wnt signaling is required for bud formation by inducing apical constriction during the pseudoglandular stage, whereas loss of Wnt signaling is necessary for air sac formation in the canalicular-saccular stages.

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  44. Coordinately Co-opted Multiple Transposable Elements Constitute an Enhancer for wnt5a Expression in the Mammalian Secondary Palate Reviewed

    Hidenori Nishihara, Naoki Kobayashi, Chiharu Kimura-Yoshida, Kuo Yan, Olga Bormuth, Qiong Ding, Akiko Nakanishi, Takeshi Sasaki, Mika Hirakawa, Kenta Sumiyama, Yasuhide Furuta, Victor Tarabykin, Isao Matsuo, Norihiro Okada

    PLoS Genetics   Vol. 12 ( 10 ) page: e1006380   2016.10

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    Acquisition of cis-regulatory elements is a major driving force of evolution, and there are several examples of developmental enhancers derived from transposable elements (TEs). However, it remains unclear whether one enhancer element could have been produced via cooperation among multiple, yet distinct, TEs during evolution. Here we show that an evolutionarily conserved genomic region named AS3_9 comprises three TEs (AmnSINE1, X6b_DNA and MER117), inserted side-by-side, and functions as a distal enhancer for wnt5a expression during morphogenesis of the mammalian secondary palate. Functional analysis of each TE revealed step-by-step retroposition/transposition and co-option together with acquisition of a binding site for Msx1 for its full enhancer function during mammalian evolution. The present study provides a new perspective suggesting that a huge variety of TEs, in combination, could have accelerated the diversity of cis-regulatory elements involved in morphological evolution.

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  45. Coordinately Co-opted Multiple Transposable Elements Constitute an Enhancer for wnt5a Expression in the Mammalian Secondary Palate Reviewed

    Hidenori Nishihara, Naoki Kobayashi, Chiharu Kimura-Yoshida, Kuo Yan, Olga Bormuth, Qiong Ding, Akiko Nakanishi, Takeshi Sasaki, Mika Hirakawa, Kenta Sumiyama, Yasuhide Furuta, Victor Tarabykin, Isao Matsuo, Norihiro Okada

    PLOS GENETICS   Vol. 12 ( 10 )   2016.10

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    Acquisition of cis-regulatory elements is a major driving force of evolution, and there are several examples of developmental enhancers derived from transposable elements (TEs). However, it remains unclear whether one enhancer element could have been produced via cooperation among multiple, yet distinct, TEs during evolution. Here we show that an evolutionarily conserved genomic region named AS3_9 comprises three TEs (AmnSINE1, X6b_DNA and MER117), inserted side-by-side, and functions as a distal enhancer for wnt5a expression during morphogenesis of the mammalian secondary palate. Functional analysis of each TE revealed step-by-step retroposition/transposition and co-option together with acquisition of a binding site for Msx1 for its full enhancer function during mammalian evolution. The present study provides a new perspective suggesting that a huge variety of TEs, in combination, could have accelerated the diversity of cis-regulatory elements involved in morphological evolution.

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  46. Involvement of Ca2+-Dependent Hyperpolarization in Sleep Duration in Mammals Reviewed

    Fumiya Tatsuki, Genshiro A. Sunagawa, Shoi Shi, Etsuo A. Susaki, Hiroko Yukinaga, Dimitri Perrin, Kenta Sumiyama, Maki Ukai-Tadenuma, Hiroshi Fujishima, Rei-ichiro Ohno, Daisuke Tone, Koji L. Ode, Katsuhiko Matsumoto, Hiroki R. Ueda

    NEURON   Vol. 90 ( 1 ) page: 70 - 85   2016.4

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    The detailed molecular mechanisms underlying the regulation of sleep duration in mammals are still elusive. To address this challenge, we constructed a simple computational model, which recapitulates the electrophysiological characteristics of the slow-wave sleep and awake states. Comprehensive bifurcation analysis predicted that a Ca2+-dependent hyperpolarization pathway may play a role in slow-wave sleep and hence in the regulation of sleep duration. To experimentally validate the prediction, we generate and analyze 21 KO mice. Here we found that impaired Ca2+-dependent K+ channels (Kcnn2 and Kcnn3), voltage-gated Ca2+ channels (Cacna1g and Cacna1h), or Ca2+/calmodulin-dependent kinases (Camk2a and Camk2b) decrease sleep duration, while impaired plasma membrane Ca2+ ATPase (Atp2b3) increases sleep duration. Pharmacological intervention and whole-brain imaging validated that impaired NMDA receptors reduce sleep duration and directly increase the excitability of cells. Based on these results, we propose a hypothesis that a Ca2+-dependent hyperpolarization pathway underlies the regulation of sleep duration in mammals.

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  47. Directed Migration of Pulmonary Neuroendocrine Cells toward Airway Branches Organizes the Stereotypic Location of Neuroepithelial Bodies Reviewed

    Masafumi Noguchi, Kenta Sumiyama, Mitsuru Morimoto

    CELL REPORTS   Vol. 13 ( 12 ) page: 2679 - 2686   2015.12

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    The airway epithelium consists of diverse cell types, including neuroendocrine (NE) cells. These cells are thought to function as chemoreceptors and as a component of the stem cell niche as well as the cells of origin in small-cell lung cancer. NE cells often localize at bifurcation points of airway tubes, forming small clusters called neuroepithelial bodies (NEBs). To investigate NEB development, we established methods for 3D mapping and ex vivo 4D imaging of developing lungs. We found that NEBs localize at stereotypic positions in the bifurcation area irrespective of variations in size. Notch-Hes1 signaling contributes to the differentiation of solitary NE cells, regulating their number but not localization. Live imaging revealed that individual NE cells migrate distally to and cluster at bifurcation points, driving NEB formation. We propose that NEB development is a multistep process involving differentiation of individual NE cells and their directional migration to organize NEBs.

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  48. Circuit-dependent striatal PKA and ERK signaling underlies rapid behavioral shift in mating reaction of male mice Reviewed

    Akihiro Goto, Ichiro Nakahara, Takashi Yamaguchi, Yuji Kamioka, Kenta Sumiyama, Michiyuki Matsuda, Shigetada Nakanishi, Kazuo Funabiki

    Proceedings of the National Academy of Sciences of the United States of America   Vol. 112 ( 21 ) page: 6718 - 6723   2015.5

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    The selection of reward-seeking and aversive behaviors is controlled by two distinct D1 and D2 receptor-expressing striatal medium spiny neurons, namely the direct pathway MSNs (dMSNs) and the indirect pathway MSNs (iMSNs), but the dynamic modulation of signaling cascades of dMSNs and iMSNs in behaving animals remains largely elusive. We developed an in vivo methodology to monitor Förster resonance energy transfer (FRET) of the activities of PKA and ERK in either dMSNs or iMSNs by microendoscopy in freely moving mice. PKA and ERK were coordinately but oppositely regulated between dMSNs and iMSNs by rewarding cocaine administration and aversive electric shocks. Notably, the activities of PKA and ERK rapidly shifted when male mice became active or indifferent toward female mice during mating behavior. Importantly, manipulation of PKA cascades by the Designer Receptor recapitulated active and indifferent mating behaviors, indicating a causal linkage of a dynamic activity shift of PKA and ERK between dMSNs and iMSNs in action selection.

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  49. Lineage-Specific Conserved Noncoding Sequences of Plant Genomes: Their Possible Role in Nucleosome Positioning Reviewed

    Nilmini Hettiarachchi, Kirill Kryukov, Kenta Sumiyama, Naruya Saitou

    GENOME BIOLOGY AND EVOLUTION   Vol. 6 ( 9 ) page: 2527 - 2542   2014.9

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    Many studies on conserved noncoding sequences (CNSs) have found that CNSs are enriched significantly in regulatory sequence elements. We conducted whole-genome analysis on plant CNSs to identify lineage-specific CNSs in eudicots, monocots, angio-sperms, and vascular plants based on the premise that lineage-specific CNSs define lineage-specific characters and functions in groups of organisms. We identified 27 eudicot, 204 monocot, 6,536 grass, 19 angiosperm, and 2 vascular plant lineage-specific CNSs (lengths range from 16 to 1,517 bp) that presumably originated in their respective common ancestors. A stronger constraint on the CNSs located in the untranslated regions was observed. The CNSs were often flanked by genes involved in transcription regulation. A drop of A+T content near the border of CNSs was observed and CNS regions showed a higher nucleosome occupancy probability. These CNSs are candidate regulatory elements, which are expected to define lineage-specific features of various plant groups.

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  50. In vivo imaging reveals PKA regulation of ERK activity during neutrophil recruitment to inflamed intestines Reviewed

    Rei Mizuno, Yuji Kamioka, Kenji Kabashima, Masamichi Imajo, Kenta Sumiyama, Eiji Nakasho, Takeshi Ito, Yoko Hamazaki, Yoshihisa Okuchi, Yoshiharu Sakai, Etsuko Kiyokawa, Michiyuki Matsuda

    JOURNAL OF EXPERIMENTAL MEDICINE   Vol. 211 ( 6 ) page: 1123 - 1136   2014.6

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    Many chemical mediators regulate neutrophil recruitment to inflammatory sites. Although the actions of each chemical mediator have been demonstrated with neutrophils in vitro, how such chemical mediators act cooperatively or counteractively in vivo remains largely unknown. Here, by in vivo two-photon excitation microscopy with transgenic mice expressing biosensors based on Frster resonance energy transfer, we time-lapse-imaged the activities of extracellular signal-regulated kinase (ERK) and protein kinase A (PKA) in neutrophils in inflamed intestinal tissue. ERK activity in neutrophils rapidly increased during spreading on the endothelial cells and showed positive correlation with the migration velocity on endothelial cells or in interstitial tissue. Meanwhile, in the neutrophils migrating in the interstitial tissue, high PKA activity correlated negatively with migration velocity. In contradiction to previous in vitro studies that showed ERK activation by prostaglandin E-2 (PGE(2)) engagement with prostaglandin receptor EP4, intravenous administration of EP4 agonist activated PKA, inhibited ERK, and suppressed migration of neutrophils. The opposite results were obtained using nonsteroidal antiinflammatory drugs (NSAIDs). Therefore, NSAID-induced enteritis may be caused at least partially by the inhibition of EP4 receptor signaling of neutrophils. Our results demonstrate that ERK positively regulates the neutrophil recruitment cascade by promoting adhesion and migration steps.

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  51. GDNF and endothelin 3 regulate migration of enteric neural crest-derived cells via protein kinase A and Rac1 Reviewed

    Akihiro Goto, Kenta Sumiyama, Yuji Kamioka, Eiji Nakasyo, Keisuke Ito, Mitsuhiro Iwasaki, Hideki Enomoto, Michiyuki Matsuda

    Journal of Neuroscience   Vol. 33 ( 11 ) page: 4901 - 4912   2013.3

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    Enteric neural crest-derived cells (ENCCs) migrate from the anterior foregut in a rostrocaudal direction to colonize the entire gastrointestinal tract and to form the enteric nervous system. Genetic approaches have identified many signaling molecules regulating the migration of ENCCs
    however, it remains elusive how the activities of the signaling molecules are regulated spatiotemporally during migration. In this study, transgenic mice expressing biosensors based on Förster resonance energy transfer were generated to video the activity changes of the signaling molecules in migrating ENCCs. In an organ culture of embryonic day 11.25 (E11.25) to E13 guts, ENCCs at the rostral wavefront migrated as a cellular chain faster than the following ENCCs that formed a network. The faster-migrating cells at the wavefront exhibited lower protein kinase A (PKA) activity than did the slower-migrating trailing cells. The activities of Rac1 and Cdc42 exhibited an inverse correlation with the PKA activity, and PKA activation decreased the Rac1 activity and migration velocity. PKA activity in ENCCs was correlated positively with the distribution of GDNF and inversely with the distribution of endothelin 3 (ET-3). Accordingly, PKA was activated by GDNF and inhibited by ET-3 in cultured ENCCs. Finally, although the JNK and ERK pathways were previously reported to control the migration of ENCCs, we did not find any correlation of JNK or ERK activity with the migration velocities. These results suggest that external cues regulate the migration of ENCCs by controlling PKA activity, but not ERK or JNK activity, and argue for the importance of live imaging of signaling molecule activities in developing organs. © 2013 the authors.

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  52. Live imaging of transgenic mice expressing FRET biosensors Reviewed

    Yuji Kamioka, Kenta Sumiyama, Rei Mizuno, Michiyuki Matsuda

    Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS   Vol. 2013   page: 125 - 128   2013

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    In recent years, fluorescence imaging has received particular attention, due to increasing availabilities of fluorescent proteins and dyes, which had driven the development of novel biosensors. Genetically-encoded biosensors based on the principle of Förster resonance energy transfer (FRET) have been widely used in biology to visualize the spatiotemporal dynamics of signaling molecules. Despite the increasing multitude of these biosensors, their application has been mostly limited to cultured cells with transient biosensor expression, due to difficulties in stable expression of FRET biosensors. In this study, we report efficient generation of transgenic mouse lines expressing heritable and functional biosensors for ERK and PKA. These transgenic mice were generated by the cytoplasmic co-injection of Tol2 transposase mRNA and a circular plasmid harboring Tol2 recombination sites. Observation of these transgenic mice by two-photon excitation microscopy yielded real-time activity maps of ERK and PKA in various tissues, with greatly improved signal-to-background ratios. Our transgenic mice may be bred into diverse genetic backgrounds
    moreover, the protocol we have developed paves the way for the generation of transgenic mice that express other FRET biosensors, with important applications in the characterization of physiological and pathological signal transduction events in addition to drug development and screening. © 2013 IEEE.

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  53. A SINE-Derived Element Constitutes a Unique Modular Enhancer for Mammalian Diencephalic Fgf8 Reviewed

    Akiko Nakanishi, Naoki Kobayashi, Asuka Suzuki-Hirano, Hidenori Nishihara, Takeshi Sasaki, Mika Hirakawa, Kenta Sumiyama, Tomomi Shimogori, Norihiro Okada

    PLOS ONE   Vol. 7 ( 8 ) page: e43785   2012.8

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    Transposable elements, including short interspersed repetitive elements (SINEs), comprise nearly half the mammalian genome. Moreover, they are a major source of conserved non-coding elements (CNEs), which play important functional roles in regulating development-related genes, such as enhancing and silencing, serving for the diversification of morphological and physiological features among species. We previously reported a novel SINE family, AmnSINE1, as part of mammalian-specific CNEs. One AmnSINE1 locus, named AS071, showed an enhancer property in the developing mouse diencephalon. Indeed, AS071 appears to recapitulate the expression of diencephalic fibroblast growth factor 8 (Fgf8). Here we established three independent lines of AS071-transgenic mice and performed detailed expression profiling of AS071-enhanced lacZ in comparison with that of Fgf8 across embryonic stages. We demonstrate that AS071 is a distal enhancer that directs Fgf8 expression in the developing diencephalon. Furthermore, enhancer assays with constructs encoding partially deleted AS071 sequence revealed a unique modular organization in which AS071 contains at least three functionally distinct sub-elements that cooperatively direct the enhancer activity in three diencephalic domains, namely the dorsal midline and the lateral wall of the diencephalon, and the ventral midline of the hypothalamus. Interestingly, the AmnSINE1-derived sub-element was found to specify the enhancer activity to the ventral midline of the hypothalamus. To our knowledge, this is the first discovery of an enhancer element that could be separated into respective sub-elements that determine regional specificity and/or the core enhancing activity. These results potentiate our understanding of the evolution of retroposon-derived cis-regulatory elements as well as the basis for future studies of the molecular mechanism underlying the determination of domain-specificity of an enhancer.

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  54. The Medaka zic1/zic4 Mutant Provides Molecular Insights into Teleost Caudal Fin Evolution Reviewed

    Yuuta Moriyama, Toru Kawanishi, Ryohei Nakamura, Tatsuya Tsukahara, Kenta Sumiyama, Maximiliano L. Suster, Koichi Kawakami, Atsushi Toyoda, Asao Fujiyama, Yuuri Yasuoka, Yusuke Nagao, Etsuko Sawatari, Atsushi Shimizu, Yuko Wakamatsu, Masahiko Hibi, Masanori Taira, Masataka Okabe, Kiyoshi Naruse, Hisashi Hashimoto, Atsuko Shimada, Hiroyuki Takeda

    CURRENT BIOLOGY   Vol. 22 ( 7 ) page: 601 - 607   2012.4

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    Teleosts have an asymmetrical caudal fin skeleton formed by the upward bending of the caudal-most portion of the body axis, the ural region [1-3]. This homocercal type of caudal fin ensures powerful and complex locomotion and is regarded as one of the most important innovations for teleosts during adaptive radiation in an aquatic environment [4-6]. However, the mechanisms that create asymmetric caudal fin remain largely unknown. The spontaneous medaka (teleost fish) mutant, Double anal fin (Da), exhibits a unique symmetrical caudal skeleton that resembles the diphycercal type seen in Polypterus and Coelacanth. We performed a detailed analysis of the Da mutant to obtain molecular insight into caudal fin morphogenesis. We first demonstrate that a large transposon, inserted into the enhancer region of the zic1 and zic4 genes (zic1/zic4) in Da, is associated with the mesoderm-specific loss of their transcription. We then show that zic1/zic4 are strongly expressed in the dorsal part of the ural mesenchyme and thereby induce asymmetric caudal fin development in wild-type embryos, whereas their expression is lost in Da. Comparative analysis further indicates that the dorsal mesoderm expression of zic1/zic4 is conserved in teleosts, highlighting the crucial role of zic1/zic4 in caudal fin morphogenesis.

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  55. A Living Fossil in the Genome of a Living Fossil: Harbinger Transposons in the Coelacanth Genome Reviewed

    Jeramiah J. Smith, Kenta Sumiyama, Chris T. Amemiya

    MOLECULAR BIOLOGY AND EVOLUTION   Vol. 29 ( 3 ) page: 985 - 993   2012.3

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    Emerging data from the coelacanth genome are beginning to shed light on the origin and evolution of tetrapod genes and noncoding elements. Of particular relevance is the realization that coelacanth retains active copies of transposable elements that once served as raw material for the evolution of new functional sequences in the vertebrate lineage. Recognizing the evolutionary significance of coelacanth genome in this regard, we employed an ab initio search strategy to further classify its repetitive complement. This analysis uncovered a class of interspersed elements (Latimeria Harbinger 1-LatiHarb1) that is a major contributor to coelacanth genome structure and gene content (similar to 1% to 4% or the genome). Sequence analyses indicate that 1) each similar to 8.7 kb LatiHarb1 element contains two coding regions, a transposase gene and a gene whose function is as yet unknown (MYB-like) and 2) copies of LatiHarb1 retain biological activity in the coelacanth genome. Functional analyses verify transcriptional and enhancer activities of LatiHarb1 in vivo and reveal transcriptional decoupling that could permit MYB-like genes to play functional roles not directly linked to transposition. Thus, LatiHarb1 represents the first known instance of a harbinger-superfamily transposon with contemporary activity in a vertebrate genome. Analyses of LatiHarb1 further corroborate the notion that exaptation of anciently active harbinger elements gave rise to at least two vertebrate genes (harbi1 and naif1) and indicate that the vertebrate gene tsnare1 also traces its ancestry to this transposon superfamily. Based on our analyses of LatiHarb1, we speculate that several functional features of harbinger elements may predispose the transposon superfamily toward recurrent exaptive evolution of cellular coding genes. In addition, these analyses further reinforce the broad utility of the coelacanth genome and other "outgroup" genomes in understanding the ancestry and evolution of vertebrate genes and genomes.

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  56. A New Database (GCD) on Genome Composition for Eukaryote and Prokaryote Genome Sequences and Their Initial Analyses Reviewed

    Kirill Kryukov, Kenta Sumiyama, Kazuho Ikeo, Takashi Gojobori, Naruya Saitou

    GENOME BIOLOGY AND EVOLUTION   Vol. 4 ( 4 ) page: 501 - 512   2012

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    Eukaryote genomes contain many noncoding regions, and they are quite complex. To understand these complexities, we constructed a database, Genome Composition Database, for the whole genome composition statistics for 101 eukaryote genome data, as well as more than 1,000 prokaryote genomes. Frequencies of all possible one to ten oligonucleotides were counted for each genome, and these observed values were compared with expected values computed under observed oligonucleotide frequencies of length 1-4. Deviations from expected values were much larger for eukaryotes than prokaryotes, except for fungal genomes. Mammalian genomes showed the largest deviation among animals. The results of comparison are available online at http://esper.lab.nig.ac.jp/genome-composition-database/.

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  57. A Mammalian Conserved Element Derived from SINE Displays Enhancer Properties Recapitulating Satb2 Expression in Early-Born Callosal Projection Neurons Reviewed

    Kensuke Tashiro, Anne Teissier, Naoki Kobayashi, Akiko Nakanishi, Takeshi Sasaki, Kuo Yan, Victor Tarabykin, Lisa Vigier, Kenta Sumiyama, Mika Hirakawa, Hidenori Nishihara, Alessandra Pierani, Norihiro Okada

    PLOS ONE   Vol. 6 ( 12 ) page: e28497   2011.12

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    Short interspersed repetitive elements (SINEs) are highly repeated sequences that account for a significant proportion of many eukaryotic genomes and are usually considered "junk DNA". However, we previously discovered that many AmnSINE1 loci are evolutionarily conserved across mammalian genomes, suggesting that they may have acquired significant functions involved in controlling mammalian-specific traits. Notably, we identified the AS021 SINE locus, located 390 kbp upstream of Satb2. Using transgenic mice, we showed that this SINE displays specific enhancer activity in the developing cerebral cortex. The transcription factor Satb2 is expressed by cortical neurons extending axons through the corpus callosum and is a determinant of callosal versus subcortical projection. Mouse mutants reveal a crucial function for Sabt2 in corpus callosum formation. In this study, we compared the enhancer activity of the AS021 locus with Satb2 expression during telencephalic development in the mouse. First, we showed that the AS021 enhancer is specifically activated in early-born Satb2(+) neurons. Second, we demonstrated that the activity of the AS021 enhancer recapitulates the expression of Satb2 at later embryonic and postnatal stages in deep-layer but not superficial-layer neurons, suggesting the possibility that the expression of Satb2 in these two subpopulations of cortical neurons is under genetically distinct transcriptional control. Third, we showed that the AS021 enhancer is activated in neurons projecting through the corpus callosum, as described for Satb2+ neurons. Notably, AS021 drives specific expression in axons crossing through the ventral (TAG1(-)/NPY+) portion of the corpus callosum, confirming that it is active in a subpopulation of callosal neurons. These data suggest that exaptation of the AS021 SINE locus might be involved in enhancement of Satb2 expression, leading to the establishment of interhemispheric communication via the corpus callosum, a eutherian-specific brain structure.

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  58. Evolution of Conserved Non-Coding Sequences Within the Vertebrate Hox Clusters Through the Two-Round Whole Genome Duplications Revealed by Phylogenetic Footprinting Analysis Reviewed

    Masatoshi Matsunami, Kenta Sumiyama, Naruya Saitou

    JOURNAL OF MOLECULAR EVOLUTION   Vol. 71 ( 5-6 ) page: 427 - 436   2010.12

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    As a result of two-round whole genome duplications, four or more paralogous Hox clusters exist in vertebrate genomes. The paralogous genes in the Hox clusters show similar expression patterns, implying shared regulatory mechanisms for expression of these genes. Previous studies partly revealed the expression mechanisms of Hox genes. However, cis-regulatory elements that control these paralogous gene expression are still poorly understood. Toward solving this problem, the authors searched conserved non-coding sequences (CNSs), which are candidates of cis-regulatory elements. When comparing orthologous Hox clusters of 19 vertebrate species, 208 intergenic conserved regions were found. The authors then searched for CNSs that were conserved not only between orthologous clusters but also among the four paralogous Hox clusters. The authors found three regions that are conserved among all the four clusters and eight regions that are conserved between intergenic regions of two paralogous Hox clusters. In total, 28 CNSs were identified in the paralogous Hox clusters, and nine of them were newly found in this study. One of these novel regions bears a RARE motif. These CNSs are candidates for gene expression regulatory regions among paralogous Hox clusters. The authors also compared vertebrate CNSs with amphioxus CNSs within the Hox cluster, and found that two CNSs in the HoxA and HoxB clusters retain homology with amphioxus CNSs through the two-round whole genome duplications.

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  59. Members of a novel gene family, Gsdm, are expressed exclusively in the epithelium of the skin and gastrointestinal tract in a highly tissue-specific manner Reviewed

    Masaru Tamura, Shigekazu Tanaka, Tomoaki Fujii, Aya Aoki, Hiromitu Komiyama, Kiyoshi Ezawa, Kenta Sumiyama, Tomoko Sagai, Toshibiko Shiroishi

    GENOMICS   Vol. 89 ( 5 ) page: 618 - 629   2007.5

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    Gasdermin (Gsdm) was originally identified as a candidate causative gene for several mouse skin mutants. Several Gsdm-related genes sharing a protein domain with DFNA5, the causative gene of human nonsyndromic hearing loss, have been found in the mouse and human genomes, and this group is referred to as the DFNA5-Gasdermin domain family. However, our current comparative genomic analysis identified several novel motifs distinct from the previously reported domain in the Gsdm-related genes. We also identified three new Gsdm genes clustered on mouse chromosome 15. We named these genes collectively the Gsdm family. Extensive expression analysis revealed exclusive expression of Gsdm family genes in the epithelium of the skin and gastrointestinal tract in a highly tissue-specific manner. Further database searching revealed the presence of other related genes with a similar N-terminal motif. These results suggest that the Gsdm family and related genes have evolved divergent epithelial expression profiles. (c) 2007 Elsevier Inc. All rights reserved.

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  60. A series of ENU-induced single-base substitutions in a long-range cis-element altering Sonic hedgehog expression in the developing mouse limb bud Reviewed

    Hiroshi Masuya, Hideki Sezutsu, Yoshiyuki Sakuraba, Tomoko Sagai, Masaki Hosoya, Hideki Kaneda, Ikuo Miura, Kimio Kobayashi, Kenta Sumiyama, Aya Shimizu, Junko Nagano, Haruka Yokoyama, Satoko Kaneko, Noriko Sakurai, Yuka Okagaki, Tetsuo Noda, Shigeharu Wakana, Yoichi Gondo, Toshihiko Shiroishi

    GENOMICS   Vol. 89 ( 2 ) page: 207 - 214   2007.2

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    Mammal-fish-conserved-sequence 1 (MFCS1) is a highly conserved sequence that acts as a limb-specific cis-acting regulator of Sonic hedgehog (Shh) expression, residing 1 Mb away from the Shh coding sequence in mouse. Using gene-driven screening of an ENU-mutagenized mouse archive, we obtained mice with three new point mutations in MFCS 1: M101116, M10111 7, and M101192. Phenotype analysis revealed that M101116 mice exhibit preaxial polydactyly and ectopic Shh expression at the anterior margin of the limb buds like a previously identified mutant, M100081. In contrast, M10111 7 and M101192 show no marked abnon-nalities in limb morphology. Furthermore, transgenic analysis revealed that the M101116 and MI00081 sequences drive ectopic reporter gene expression at the anterior margin of the limb bud, in addition to the normal posterior expression. Such ectopic expression was not observed in the embryos carrying a reporter transgeDe driven by M101117. These results suggest that M101116 and M100081 affect the negative regulatory activity of MFCSI, which suppresses anterior Shh expression in developing limb buds. Thus, this study shows that gene-driven screening for ENU-induced mutations is an effective approach for exploring the function of conserved, noncoding sequences and potential cis-regulatory elements. (c) 2006 Elsevier Inc. All rights reserved.

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  61. Phylogenetic Analysis of the Mammalian Hoxc8 Non-coding Region. Reviewed

    Chang-Bae Kim, Cooduvalli S. Shashikant, Kenta Sumiyama, Chris T. Amemiya, Wayne C, H. Wang, Frank H. Ruddle

    Journal of Structural and Functional Genomics   Vol. 3: 195-199   2003

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  62. Genomic organization of the genes Gtf2ird1, Gtf2i, and Ncf1 at the mouse chromosome 5 region syntenic to the human chromosome 7q11.23 Williams syndrome critical region Reviewed

    D Bayarsaihan, J Dunai, JM Greally, K Kawasaki, K Sumiyama, B Enkhmandakh, N Shimizu, FH Ruddle

    GENOMICS   Vol. 79 ( 1 ) page: 137 - 143   2002.1

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    We have recently isolated a mouse ortholog of human GTF2IRD1 that is related to GTF2I. GTF2IRD1 and GTF2I proteins are characterized by the presence of multiple helix-loop-helix domains and a leucine zipper motif. Both paralogs are closely linked and deleted hemizygously in individuals with Williams syndrome, a dominant genetic condition characterized by unique neurocognitive and behavioral features. We have isolated and analyzed the sequence of bacterial artificial chromosome clones from the syntenic mouse chromosome 5 region that contains Gtf2ird1 and Gtf2i as well as a neighboring gene, Ncf1. Gtf1ird1 is composed of 31 exons spanning &gt; 100 kb on mouse chromosome 3 and is located between Cyln2 and Gtf2i. Gtf2i is composed of 34 exons spanning about 77 kb. Ncf1, located downstream of Gtf2i, consists of 11 exons that extend over 8 kb. The gene organization of Gtf2ird1, Gtf2i, and Ncf1 is conserved in mice and humans, although the intronic regions are more compact in the mouse genome. The helix-loop-helix repeats of Gtf2ird1 and Gtf2i are encoded separately on adjacent exons and were generated by independent genomic rearrangements. These studies contribute to our knowledge of transcription factor defects and their pathogenesis in haploinsufficiency conditions.

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  63. Genomic organization of the genes Gtf2ird1, Gtf2i, and Ncf1 at the mouse chromosome 5 region syntenic to the human chromosome 7q11.23 Williams syndrome critical region Reviewed

    D Bayarsaihan, J Dunai, JM Greally, K Kawasaki, K Sumiyama, B Enkhmandakh, N Shimizu, FH Ruddle

    GENOMICS   Vol. 79 ( 1 ) page: 137 - 143   2002.1

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    We have recently isolated a mouse ortholog of human GTF2IRD1 that is related to GTF2I. GTF2IRD1 and GTF2I proteins are characterized by the presence of multiple helix-loop-helix domains and a leucine zipper motif. Both paralogs are closely linked and deleted hemizygously in individuals with Williams syndrome, a dominant genetic condition characterized by unique neurocognitive and behavioral features. We have isolated and analyzed the sequence of bacterial artificial chromosome clones from the syntenic mouse chromosome 5 region that contains Gtf2ird1 and Gtf2i as well as a neighboring gene, Ncf1. Gtf1ird1 is composed of 31 exons spanning &gt; 100 kb on mouse chromosome 3 and is located between Cyln2 and Gtf2i. Gtf2i is composed of 34 exons spanning about 77 kb. Ncf1, located downstream of Gtf2i, consists of 11 exons that extend over 8 kb. The gene organization of Gtf2ird1, Gtf2i, and Ncf1 is conserved in mice and humans, although the intronic regions are more compact in the mouse genome. The helix-loop-helix repeats of Gtf2ird1 and Gtf2i are encoded separately on adjacent exons and were generated by independent genomic rearrangements. These studies contribute to our knowledge of transcription factor defects and their pathogenesis in haploinsufficiency conditions.

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  64. Gene diversity of chimpanzee ABO blood group genes elucidated from exon 7 sequences Reviewed

    K Sumiyama, T Kitano, R Noda, RE Ferrell, N Saitou

    GENE   Vol. 259 ( 1-2 ) page: 75 - 79   2000.12

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    Human and non-human primate ABO blood group genes show relatively large numbers of nucleotide differences. In this study, we determined exon 7 sequences for 10 individuals of common chimpanzee and for four individuals of bonobo to estimate nucleotide diversities among them. Sequence data showed the existence of chimpanzee specific 9-base deletion in the beginning of the exon 7 coding region. From a phylogenetic network of exon 7 sequences of ABO blood group genes for human, common chimpanzee, bonobo and gorilla, effects of parallel substitutions and/or some kinds of convergent events are inferred in the chimpanzee lineage. We also estimated nucleotide diversities for common chimpanzee and bonobo ABO blood group genes, and these values were 0.4% and 0.2%, respectively. These values are higher than that of most human genes. (C) 2000 Elsevier Science B.V. All rights reserved.

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  65. Gene diversity of chimpanzee ABO blood group genes elucidated from intron 6 sequences Reviewed

    T Kitano, R Noda, K Sumiyama, RE Ferrell, N Saitou

    JOURNAL OF HEREDITY   Vol. 91 ( 3 ) page: 211 - 214   2000.5

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    The human and nonhuman primate ABO blood group gene shows relatively large numbers of nucleotide differences around the exon 7 region. In this study we determined intron 6 sequences for 9 alleles of common chimpanzee and for 3 alleles of bonobo to estimate nucleotide diversities among them. Sequence length polymorphisms are observed in this region as a repeat appears one to five times. From a phylogenetic network of intron 6 sequences of ABO blood group genes for humans, common chimpanzee, and bonobo, parallel substitutions and/or some kinds of convergent events are predicted in the chimpanzee lineage. We also estimated nucleotide diversities for common chimpanzee and bonobo ABO blood group genes; these values were 0.219% and 0.208%, respectively.

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  66. Conserved evolution of the Rh50 gene compared to its homologous Rh blood group gene Reviewed

    T Kitano, K Sumiyama, T Shiroishi, N Saitou

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   Vol. 249 ( 1 ) page: 78 - 85   1998.8

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    We have sequenced the complete coding region of the Rh blood group gene for mouse and rat and that of Rh-related 50 kD glycoprotein (Rh50) for mouse, rat, and crab-eating macaque. Phylogenetic analyses of Rh and Rh50 amino acid sequences indicate that the Rh50 gene has been evolving about two times more slowly than the Rh blood group gene in both primates and rodents. This conservative nature of the Rh50 gene suggests its relative importance to the Rh blood group gene. The time of gene duplication that produced the Rh and Rh50 genes was estimated to be about 240-310 million years ago. We also conducted window analyses of synonymous and nonsynonymous nucleotide substitutions for those two genes. Some peaks where nonsynonymous substitutions are higher than synonymous ones were located on outer membrane regions. This suggests the existence of positive Darwinian selection on Rh and Rh50 genes through host-parasite interactions. (C) 1998 Academic Press.

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  67. Human class III POU genes, POU3F1 and POU3F3, map to Chromosomes 1p34.1 and 3p14.2 Reviewed

    K Sumiyama, K Washio-Watanabe, T Ono, MC Yoshida, T Hayakawa, S Ueda

    MAMMALIAN GENOME   Vol. 9 ( 2 ) page: 180 - 181   1998.2

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    DOI: 10.1007/s003359900721

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  68. A high sequence variety in the immunoglobulin C-alpha hinge region among old world monkeys Reviewed

    K Sumiyama, S Kawamura, O Takenaka, S Ueda

    ANTHROPOLOGICAL SCIENCE   Vol. 106 ( 1 ) page: 31 - 39   1998.1

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    Immunoglobulin Ca gene encodes a constant region of heavy-chain of IgA antibody, and the hinge region is located between CHI domain and CH2 domain. The hinge region functions to increase efficiency of antigen binding by varying distance between two antigen recognition sites. The constant region of ISA has been considered to be conservative, but we previously reported that immunoglobulin C alpha genes of great apes showed evolutionary hypervariability mainly in the hinge region (Kawamura and others, 1990). To know whether this hypervariability is also the case among Old World monkeys, we carried out PCR-SSCP analysis for macaque, baboon, and leaf monkey. The result clearly showed evolutionary hypervariability in the hinge region among Old World monkeys. Adding to this inter-species variability, intra-species variabilities were also observed in multiple species such as rhesus macaque, crab-eating macaque, Assamese macaque, and hamadryas baboon. Furthermore, polymorphism was likely shared by multiple macaque species (trans-species polymorphism). These results suggest the indispensability of hypervariability in the hinge region for these animals. Some kind of positive selection, like the overdominance at the MHC loci (Klein and others, 1993) might be responsible for this hypervariability.

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  69. Nucleotide compositional constraints on genomes generate alanine-, glycine-, and proline-rich structures in transcription factors Reviewed

    Y Nakachi, T Hayakawa, H Oota, K Sumiyama, L Wang, S Ueda

    MOLECULAR BIOLOGY AND EVOLUTION   Vol. 14 ( 10 ) page: 1042 - 1049   1997.10

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    Correlation between amino acid composition and nucleotide composition is examined. Class III POU transcription factors having higher third GC contents showed higher contents of alanine, glycine, and proline residues encoded by GC-rich nucleotides, and vice versa. This correlation was observed even among various types of transcription factors from vertebrates and invertebrates regardless of functional and structural constraints inherent to each protein. Furthermore, reptile class III POU sequences revealed no evolutionary directionality increasing the GC contents from cold-to warm-blooded vertebrates.

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Books 9

  1. ヒトゲノム事典

    隅山 健太( Role: Contributor ,  16.5章担当)

    株式会社一色出版  2021.11  ( ISBN:9784910389127

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  2. 図解人類の進化 : 猿人から原人、旧人、現生人類へ

    斎藤, 成也, 海部, 陽介, 米田, 穣, 隅山, 健太

    講談社  2021.11  ( ISBN:9784065261361

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  3. 遺伝子が語る生命38億年の謎 - なぜ、ゾウはネズミより長生きか? 国立遺伝学研究所 (編) 第Ⅱ部 人類進化の謎 第8章 ヒトゲノムの暗黒部分の謎―どのような遺伝子の変化がヒトを進化させてきたのか?

    隅山 健太( Role: Contributor ,  80-88)

    悠書館  2014.6  ( ISBN:9784903487922

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  4. 遺伝子図鑑 国立遺伝学研究所「遺伝子図鑑」編集委員会編 7-12 遺伝子重複

    隅山 健太( Role: Contributor ,  160-161)

    2013.10  ( ISBN:9784903487793

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  5. 進化学事典 (日本進化学会編)

    隅山 健太( Role: Contributor ,  17-3 転写と翻訳調節)

    共立出版  2012.4  ( ISBN:9784320057777

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  6. <series モデル動物利用マニュアル> 生物機能モデルと新しいリソース・ リサーチツール

    隅山健太, 川上浩一( Role: Contributor ,  第6節 新しい生殖工学技術 第4項 トランスポゾンを使った 新しい高効率トランスジェニックマウス作製法)

    エル・アイ・シー  2011  ( ISBN:9784900487482

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  7. 「絵でわかる人類の進化」斎藤成也編

    斎藤成也, 海部陽介, 米田穣, 隅山健太( Role: Contributor ,  第2章 26-44頁)

    講談社  2009  ( ISBN:9784061547599

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  8. 絵でわかる人類の進化

    斎藤 成也, 海部 陽介, 米田 穣, 隅山 健太, 講談社サイエンティフィク

    講談社  2009  ( ISBN:9784061547599

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  9. 脊椎動物の比較ゲノム:遺伝子間領域の比較解析 細胞工学別冊:比較ゲノム学から読み解く生命システム 監修 藤山秋佐夫

    秀潤社  2007  ( ISBN:9784879623607

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MISC 19

  1. Functional analyses of Dlx cluster genes using genome-editing methods Invited

    Akira Tanave, Kenta Sumiyama

    Medical Science Digest   Vol. 45 ( 9 ) page: 50 - 51   2019.7

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  2. トリプルCRISPR法による第一世代両アリル完全ノックアウトマウス作製

    隅山健太, 砂川玄志郎, 鵜飼(蓼沼)磨貴, ディミトリー ペリン, 上田泰己

    日本実験動物学会総会講演要旨集   Vol. 64th   page: 228   2017.4

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  3. Triple-target CRISPR enabled almost perfect whole-body bi-allelic knockouts at first generation

    Kenta Sumiyama, Genshiro Sunagawa, Maki Ukai-Tadenuma, Dimitri Perrin, Hiroki Ueda

    GENES & GENETIC SYSTEMS   Vol. 91 ( 6 ) page: 334 - 334   2016.12

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  4. トリプルCRISPR法による第一世代での両アリル完全ノックアウトマウス作製

    隅山健太, 砂川玄志郎, 鵜飼(蓼沼)磨貴, PERRIN Dimitri, 上田泰己

    日本遺伝学会大会プログラム・予稿集   Vol. 88th   page: 111   2016.8

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  5. High expression of PACAP gene and the molecular mechanism found in wild-mouse strain showing elevated anxiety-like behavior

    Akira Tanave, Tsuyoshi Koide, Kenta Sumiyama, Aki Takahashi

    INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY   Vol. 19   page: 53 - 53   2016.6

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  6. トリプルCRISPR法による第一世代での両アリル完全ノックアウトマウス作製

    隅山健太, 砂川玄志郎, 鵜飼(蓼沼)磨貴, DIMITRI Perrin, DIMITRI Perrin, 上田泰己

    日本細胞生物学会大会(Web)   Vol. 68th   page: ROMBUNNO.T3‐1 (WEB ONLY)   2016

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  7. 高活性型TALE蛋白質の開発とゲノム配列ライブイメージングへの応用 Reviewed

    池田 一穂, 寺原 陽子, 隅山 健太, 岡田 康志

    日本細胞生物学会大会講演要旨集   Vol. 67回   page: 185 - 185   2015.6

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  8. Possible acquisition of novel cis-regulatory function by gene duplication in vertebrate body plan evolution

    Kenta Sumiyama

    GENES & GENETIC SYSTEMS   Vol. 88 ( 6 ) page: 332 - 332   2013.12

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  9. Analysis of conserved noncoding sequences (CNSs) in plants

    Nilmini Hettiarachchi, Kirill Kryukov, Kenta Sumiyama, Naruya Saitou

    GENES & GENETIC SYSTEMS   Vol. 87 ( 6 ) page: 422 - 422   2012.12

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  10. Close Up実験法 Series207 Tol2トランスポゾンを用いた画期的なトランスジェニックマウス作製法

    隅山健太, 川上浩一

    実験医学   Vol. 28 ( 16 ) page: 2653-2660 - 2660   2010.10

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    J-GLOBAL

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  11. Evolutionary genomic analysis of primates and mammals

    Naruya Saitou, Hyung-Cheol Kim, Kenta Sumiyama, Mahoko Takahashi, Waka Masuyama

    GENES & GENETIC SYSTEMS   Vol. 82 ( 6 ) page: 503 - 503   2007.12

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  12. Life system observed from genome: Approach from comparison genome (No.3). Comparison genome of vertebrate: Comparison analysis of regions between genes.

    隅山健太, 斎藤成也

    細胞工学   Vol. 24 ( 10 ) page: 1108-1111 - 1111   2005.9

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    J-GLOBAL

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  13. 多彩な機能をもつ転写調節因子ホメオタンパク質 分化多能性の維持から形態形成の指令,進化の解明,疾患への関与まで Hox遺伝子クラスタの進化 脊椎動物の誕生からヒトまで

    斎藤成也, 隅山健太

    実験医学   Vol. 22 ( 12 ) page: 1677-1683 - 1683   2004.8

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    J-GLOBAL

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  14. 1章 ヒトゲノムの全貌 ヒトの遺伝子構成 主な遺伝子ファミリーの特徴 HOX遺伝子

    隅山健太, 斎藤成也

    Mol Med   Vol. 41   page: 91-93 - 93   2004.6

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    J-GLOBAL

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  15. ヒトゲノムー生命システムの理解と医学への展開ー Hox遺伝子.

    隅山健太, 斎藤成也

    中山書店・MOLECULAR MEDICINE臨時増刊号   Vol. 41   page: 91 - 93   2004

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  16. The evolution of CIS-regulatory elements in the DLX3-DLX-7 cluster.

    K Sumiyama, FH Ruddle

    AMERICAN ZOOLOGIST   Vol. 39 ( 5 ) page: 78A - 78A   1999

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  17. Evolution of ABO blood group genes in primates

    NODA R., KITANO T., SUMIYAMA K., TAKENAKA O., SAITOU N.

      Vol. 21   page: 209 - 209   1998.12

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    CiNii Books

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  18. Evolution of rodents Rh blood group genes

    KITANO Takashi, SUMIYAMA Kenta, SHIROISHI Toshihiko, SAITOU Naruya

      Vol. 21   page: 342 - 342   1998.12

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    CiNii Books

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  19. Possible ecological selection in immunoglobulin C alpha gene of old world monkeys

    K Sumiyama, S Kawamura, S Ueda

    ANTHROPOLOGICAL SCIENCE   Vol. 104 ( 2 ) page: IV07 - IV07   1996.4

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▼display all

Presentations 101

  1. "The analysis of genomic regulation of the mouse Dlx3-Dlx7 cluster." International conference

    Kenta Sumiyama, Frank H. Ruddle

    14th International Congress of Developmental Biology. Kyoto, Japan  2001.7 

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  2. "Positive selection in the primate IgA hinge region." International conference

    Kenta Sumiyama, Shohji Kawamura, Shintaroh Ueda

    1997.6 

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  3. "POA-380: Inferring ancestral state before WGD from enhancers and CTCF/cohesin loops in developmental genes." International conference

    SUMIYAMA Kenta

    SMBE 2018 at Yokohama: 50th anniversary of the neutral theory of molecular evolution  2018.7 

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  4. "Higher expression of Adcyap1gene is associated with altered behavioral and prolonged physiological responses to stress in wild-derived MSM mice." International conference

    Akira Tanave, Aki Takahashi, Kenta Sumiyama, Tsuyoshi Koide

    29th Annual Conference of the International Mammalian Genome Society  2015.11.8 

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  5. "Functional Analysis Of The 80Kb DLX3-7 Gene Cluster Using pClasper System And Transgenic Mouse."

    Kenta Sumiyama, Frank H. Ruddle

    2000.12 

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  6. "Analysis of cis-regulatory elements in the Dlx3-Dlx7 gene cluster by using the transgenic mouse system." International conference

    Kenta Sumiyama, Frank H. Ruddle

    Gordon Research Conference, Hayama, Japan  1999.10 

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  7. "Allelic genealogy of ABO blood group locus in chimpanzee." International conference

    Kenta Sumiyama, Shintaroh Ueda, Robert Ferrell, Naruya Saitou

    The Fourth Annual Meeting of the Society for Molecular Biology and Evolution (SMBE4), Tucson, USA  1996.6 

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  8. "A simple and highly efficient transgenesis method in mice with the Tol2 transposon system and cytoplasmic microinjection." International conference

    Kenta Sumiyama, Koichi Kawakami, Kazuhiro Yagita

    43rd Annual Meeting for the Japanese Society of Developmental Biologists, 2010年6月, Kyoto, Japan.  2010.6 

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  9. "The evolution of cis-regulatory elements in the Dlx3 and Dlx7 cluster." International conference

    Kenta Sumiyama, Frank H. Ruddle

    Society for Integrative and comparative biology, 2000 Annual Meeting. Atlanta, Georgia, USA  2000.1 

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  10. 「初代マウスで表現型解析可能なゲノム編集技術の開発と進化学研究への応⽤」

    隅山 健太

    第5回ケモビ研究会  2018.3 

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  11. 「トリプルCRISPR法による交配無しでのダブルノックアウト、トリプルノックアウトマウス作製」

    田邉 彰, 隅山 健太

    大阪大学大学院医学系研究科 第12回若手研究フォーラム  2019.2 

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  12. 「トリプルCRISPR 法による第一世代での両アリル完全ノックアウトマウス作製」

    隅山 健太, 砂川 玄志郎, 鵜飼(蓼沼) 磨貴, ディミトリー ペリン, 上田 泰己

    第68回日本細胞生物学会大会、京都テルサ  2016.6.15 

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  13. 「トリプル CRISPR 法による第一世代での両アリル完全ノックアウトマウス作製」第30回モロシヌス研究会

    隅山 健太

    第30回モロシヌス研究会、ホテルグリーンピア南阿蘇  2017.6 

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  14. 「トリプル CRISPR 法による第一世代での両アリル完全ノックアウトマウス作製」

    隅山 健太

    日本ゲノム編集学会第2回大会、千里ライフサイエンスセンター、大阪府豊中市  2017.6 

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  15. 「トリプル CRISPR 法による第一世代での両アリル完全ノックアウトマウス作製 〜交配なしでのマウス表現型解析〜 」

    隅山 健太

    人類学談話会、東京大学理学部本郷キャンパス  2017.8 

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  16. 「ほ乳類Dlx3-7遺伝子クラスター発現調節領域に起きた過去の急速な進化」

    隅山 健太

    第8回進化学会大会、東京  2006.8 

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  17. 「ついに明らかになるのか?動物特有の遺伝子発現調節機構と進化可能性」

    隅山 健太

    遺伝研研究集会「分子進化学の現状と今後の展望」  2016.8.20 

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  18. 「TALE蛋白DNA結合ドメインの改変による高活性TALEN」

    池田 一穂, 寺原 陽子, 隅山 健太, 宮下 尚之, 岡田 康志

    第4回ゲノム編集研究会、広島国際会議場ダリア  2014.10.6 

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  19. 「Dlx遺伝子クラスターにおけるcisエレメントの進化」

    隅山 健太

    第7回進化学会大会、仙台  2005.8 

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  20. “Super-active TALEN with improved stability at 37 degree Celsius enables highly efficient and homogeneous gene knockout in mammalian embryos” International conference

    Ikeda, K, Y. Terahara, K. Sumiyama, N. Miyashita, Y. Sugita, Y. Okada

    the 2014 ASCB/IFCB meeting, Pennsylvania Convention Center, Philadelphia, PA, USA  2014.12.8 

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  21. “Genome editing technologies for gene knockout phenotyping on founder mice.”

    SUMIYAMA Kenta

    The present and the future of synthetic biology, RIKEN KOBE CDB  2015.12.3 

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  22. “Development and application of improved TALE protein.”

    Kazuho Ikeda, Yoko Terahara, Kenta Sumiyama, Yasushi Okada

    2015.9.13 

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  23. “Cis-regulatory landscape and evolution of the mammalian Dlx genes.” International conference

    SUMIYAMA Kenta

    International Symposium "Genetic Regulation of Development" Commemorative of 27th International Prize for Biology, 2011 Celebrating Dr.Eric H.Davidson  2011.11 

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  24. Two Regulatory Elements in ParaHox Clusters Derived from Whole Genome Duplication

    The 16th CDB Meeting "Cis-sequence Regulation and its Evolution"  2008 

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  25. Toolkit genes, cis-regulatory modules, turnover, and evolvability

    隅山 健太

    第1回 Tokyo Vertebrate Morphology Meeting  2011.11 

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  26. Theria-specific evolution in both coding and noncoding region of the Dlx4 gene. International conference

    SUMIYAMA Kenta

    Annual Meeting for the Society for Molecular Biology and Evolution (SMBE 2011), Kyoto, Japan.  2011.7 

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  27. The Genetic Basis For Primate Evolution At Cis-Regulatory System Level. International conference

    SUMIYAMA Kenta

    International Primatological Society XXIII Congress, Kyoto, Japan.  2010.9 

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  28. Characterization of the Fgf8 cis-regulatory elements derived from a SINE and possibility of participation in the mammal-specific brain formation

    中西晶子, 佐々木剛, 小林直樹, 西原秀典, 隅山健太, 斉藤成也, 岡田典弘

    日本分子生物学会年会講演要旨集  2009 

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  29. Molecular evolution research on Rh blood type gene and its homologous gene.

    北野誉, 隅山健太, 斎藤成也, 城石俊彦, 嵯峨井知子

    日本遺伝学会大会プログラム・予稿集  1997.11 

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  30. Evolution of Rh Blood Type Genes and Their Homologous Genes.

    北野誉, 隅山健太, 斎藤成也, 城石俊彦, 嵯峨井知子

    日本分子生物学会年会プログラム・講演要旨集  1997.12 

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  31. Next generation mammalian genetics

    SUMIYAMA Kenta

    Osaka Univ. FBS Special lecture  2019.2 

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  32. p53によるATMのフィードバック制御:FRETバイオセンサーを用いた解析

    林亜里香, 後藤明弘, 隅山健太, 松田道行, CANDEIAS Marco

    日本分子生物学会年会プログラム・要旨集(Web)  2012 

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  33. Origins of cis-regulatory elements in "Junk Yard" International conference

    SUMIYAMA Kenta

    NIG research meeting「Evolution of Junk DNAs」, Mishima  2013.7 

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  34. Known Regulatory Elements. International conference

    Kenta Sumiyama, Frank H. Ruddle

    Hox Workshop, Whitehead Institute for Genomic Research, Massachusetts, USA  2001.6 

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  35. In vivo FRET Imaging:分子活性と細胞動態を同時に観察する新しい研究手法

    松田道行, 水野礼, 平塚拓也, 隅山健太, 坂井義治, 上岡裕治

    日本免疫学会総会・学術集会記録  2014.11.18 

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  36. Identification and evolutionary origin of a limb enhancer in the Dlx3-7 bigene cluster.

    日本進化学会第9回大会  2007 

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  37. Identification and evolutionary origin of a limb enhancer in the Dlx3-7 bigene cluster.

    Annual Meeting of the Society for Molecular Biology and Evolution  2007 

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  38. Highly conserved non-coding sequences in ParaHox clusters drive reporter gene expression similar to endogenous ParaHox Gsh genes.

    Annual Meeting of the Society for Molecular Biology and Evolution  2008 

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  39. Gsxホメオボックス遺伝子のパラロガス転写調節領域の機能と進化

    SUMIYAMA Kenta

    2012.8 

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  40. Gene duplication and functional diversification in mammalian Dlx genes. International conference

    SUMIYAMA Kenta

    International Mammalian Symposium  2004.2 

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  41. Functional genomic analysis of cis-regulation in mammalian Dlx gene system. International conference

    SUMIYAMA Kenta

    Symposium on Comparative Genomics, Taejon, Korea.  2004.4 

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  42. Functional evaluation of cis-regulatory elements and their evolution in the vertebrate Dlx3-7 bigene cluster. International conference

    SUMIYAMA Kenta

    NAIST Global COE International Symposium 2010: Plasticity in Development and Evolution, Nara, Japan.  2010.11 

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  43. Functional cis-element analysis of Dlx gene system by using multiple species genome sequence information. International conference

    SUMIYAMA Kenta

    International Symposium on “Dynamics of Developmental Systems” Kisarazu, Japan.  2005.11 

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  44. Functional analysis of evolutionary conserved cis-regulatory elements in the Dlx3-7 gene cluster by using transgenic mouse system. International conference

    Kenta Sumiyama, Frank H. Ruddle

    Annual Meeting of the Society for Molecular Biology and Evolution (SMBE 2000)  2000.6 

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  45. Finding functional elements in non-coding region by comparative genome study. International conference

    SUMIYAMA Kenta

    KOGO 2005 Annual Meeting, Seoul, Korea.  2005.9 

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  46. Evolutionary study of the vertebrate cis-regulatory elements in development with special reference to the Dlx gene system.

    International Conference on Mathematics, Evoluton AND Development, Shanghai  2010 

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  47. Evolution of Cis-regulatory Elements in the Vertebrate Dlx Bigene Cluster System International conference

    SUMIYAMA Kenta

    The 8th Okazaki Biology Conference -Speciation and Adaptation II - Environment and Epigenetics -, Okazaki, Japan.  2012.3 

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  48. Evolution of Cis-regulatory Elements in the Vertebrate Dlx Bigene Cluster System International conference

    SUMIYAMA Kenta

    Symposium of Genomic Conservation and Diversity of Organisms ~Beyond the NGS time of Life Science~, Tainan, Taiwan.  2011.12 

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  49. Dlx4遺伝子の進化学的解析とゲノム編集による実験検証

    隅山健太

    日本進化学会大会プログラム・講演要旨集(Web)  2017.8.24 

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  50. Dlx3-7遺伝子クラスターの四肢エンハンサーの同定およびその進化的起源

    第40回日本発生生物学会大会  2007 

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  51. Cis-regulatory Elements and Evolution Elucidated by Genomic Sequence Comparison of the Vertebrate Dlx3-7 Bigene Clusters.

    The 16th CDB Meeting "Cis-sequence Regulation and its Evolution"  2008 

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  52. Cis-element evolution of the Dlx genes as an underlying mechanism in toolkit gene co-option in vertebrate appendages.

    The International Darwin Bicentennial Symposium  2009 

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  53. “Cis-element evolution elucidated by genomic sequence comparison of the vertebrate Dlx3-7 bigene clusters.” International conference

    SUMIYAMA Kenta

    Annual Meeting of the Society for Molecular Biology and Evolution, Barcelona  2008.6 

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  54. An adaptive evolution of the Immunoglobulin C alpha gene in hominoids and other primates. International conference

    Kenta Sumiyama, Shohji Kawamura, Shintaroh Ueda

    THE TRI-NATIONAL MEETING ON MOLECULAR EVOLUTION  1997.6 

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  55. A simple and highly efficient transgenesis method in mice with the Tol2 transposon system and cytoplasmic microinjection.

    隅山 健太, 川上 浩一, 八木田 和弘

    第33回日本分子生物学会年会・第83回日本生化学会大会合同大会  2010.12 

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  56. A high sequence variation in immunoglobulin C alpha gene hinge region in macaques. International conference

    Kenta Sumiyama, Shintaroh Ueda

    International Symposium Evolution of Asian Primates  1996.8 

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  57. "Triple-target CRISPR enabled almost perfect whole-body bi-allelic knockouts at first generation" International conference

    SUMIYAMA Kenta

    Genome Editing Towards Medicinal Applications, 第9回武田科学振興財団薬科学シンポジウム  2018.2 

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  58. "Triple-target CRISPR enabled almost perfect whole-body bi-allelic knockouts at first generation" International conference

    SUMIYAMA Kenta

    JSDB Special Symposium: Frontier of Developmental Biology Hosted by JSDB  2016.6.2 

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  59. 「哺乳類分子進化研究におけるゲノム編集技術の有用性と残された問題点」

    隅山 健太

    遺伝研研究集会「ゲノム編集時代の分子進化」  2014.6.28 

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  60. 高活性型TALE蛋白質の開発とゲノム配列ライブイメージングへの応用

    池田一穂, 寺原陽子, 隅山健太, 岡田康志

    日本細胞生物学会大会要旨集  2015.6.5 

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  61. 高不安様行動を示す野生マウス系統におけるPACAPの高発現と分子機構

    田邉彰, 田邉彰, 高橋阿貴, 高橋阿貴, 隅山健太, 小出剛, 小出剛

    日本神経精神薬理学会プログラム・抄録集  2016 

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  62. Analysis of positive selection evolution in immunoglobulin IgA hinge region of Primates.

    隅山健太, 植田信太郎, 斎藤成也

    日本遺伝学会大会プログラム・予稿集  1997.11 

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  63. Positive Selection in the Primate IgA Hinge Region.

    隅山健太, 河村正二, 斎藤成也, 植田信太郎

    日本分子生物学会年会プログラム・講演要旨集  1997.12 

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  64. Evolution of ABO blood group genes in Primates.

    野田令子, 北野誉, 隅山健太, 竹中修, 斎藤成也

    日本遺伝学会大会プログラム・予稿集  1997.11 

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  65. 霊長類におけるABO式血液型遺伝子の進化

    野田令子, 北野誉, 隅山健太, 竹中修, 斎藤成也

    日本分子生物学会年会プログラム・講演要旨集  1998.11 

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  66. 霊長類におけるABO式血液型遺伝子の進化

    野田令子, 北野誉, 隅山健太, 竹中修, 斎藤成也

    日本分子生物学会年会プログラム・講演要旨集  1998.11 

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  67. Evolution of ABO blood groupe genes in primates.

    野田令子, 北野誉, 隅山健太, 竹中修, 斎藤成也

    日本分子生物学会年会プログラム・講演要旨集  1997.12 

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  68. 鋤鼻器のDlx3 /Dlx4 遺伝子発現に必須なシス調節モジュールクラスターの発見

    田邉 彰, 隅山 健太

    日本遺伝学会第93回大会(オンライン)  2021.9.9 

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  69. 遺伝子間領域におけるcis-elementの進化

    国立遺伝学研究所研究会<中立進化論の現在>  2008 

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  70. 遺伝子改変マウスを用いた非コード領域の進化的研究

    隅山健太

    日本遺伝学会大会プログラム・予稿集  2017.8.28 

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  71. Correlation between GC content and homopolymeric amino acid repeats in the brain-specific transcription factor genes.

    仲地豊, 早川敏之, 太田博樹, WANG L, 隅山健太, 植田信太郎

    日本分子生物学会年会プログラム・講演要旨集  1997.12 

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  72. 脊椎動物祖先まで遡る起源の古いcis-element機能の哺乳類個体でのin vivo 定量評価

    隅山 健太, 田邉 彰

    日本遺伝学会第93回大会(オンライン)  2021.9.9 

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  73. Evolution of vertebrate morphogenetic gene regulatory mechanisms: Dlx gene cluster as an example

    SUMIYAMA Kenta

    2019.9.13 

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  74. 脊椎動物ボディプラン進化における遺伝子重複によるシス転写調節機構新機能獲得進化の可能性

    隅山健太

    日本遺伝学会大会プログラム・予稿集  2013.9.19 

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  75. 脊椎動物におけるDlx遺伝子エンハンサーの分子進化

    隅山 健太

    第11回日本進化学会大会  2009 

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  76. 胎盤形成に関与するDlx4 遺伝子の獣亜綱 (Theria) 特異的なタンパク質コード領域および転写制御領域における分子進化と機能解析

    隅山 健太

    日本進化学会第13回大会 京都  2011.7 

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  77. 組織細胞間コミュニケーションのライブイメージングに資する細胞形態マーカー発現マウスの作成

    今西彩子, 小松直貴, 隅山健太, 松田道行, 松田道行

    日本細胞生物学会大会(Web)  2016 

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  78. 系統フットプリント法を応用した遺伝子間領域cis-elementの進化速度解析の試み

    日本進化学会第10回大会  2008 

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  79. 第2回 中高生のためのオンライン特別授業 「最近話題の あの技術 この技術 驚異の発見・発明! ゲノム編集

    隅山 健太

    理化学研究所 神戸キャンパス 第2回 中高生のためのオンライン特別授業  2021.1.15 

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  80. 発生調節遺伝子群Dlx3‐7の発現調節cis‐因子の同定とその進化

    隅山健太, KIM H‐C, 斎藤成也

    日本分子生物学会年会プログラム・講演要旨集  2004.11.25 

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  81. Possibility of the positive selection evolution of the Old World monkies in an immunoglobulin C.ALPHA. gene hinge region.

    隅山健太, 植田信太郎

    日本遺伝学会大会プログラム・予稿集  1996.10 

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  82. 哺乳類および霊長類に特有な高度に保存されている塩基配列の進化

    斎藤成也, KIM Hyung‐Cheol, 高橋真保子, 隅山健太

    生化学  2008 

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  83. 哺乳類Gsx1, Gsx2ホメオボックス遺伝子シス発現調節因子の進化的および機能的解析

    隅山 健太

    第46回日本発生生物学会年会  2013.5 

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  84. 哺乳類Dlx遺伝子クラスターにおけるシス制御因子の機能解析と進化

    隅山健太

    日本分子生物学会年会プログラム・要旨集(Web)  2016.12.1 

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  85. 人類進化におけるゲノム非コード領域転写調節機能進化解析の試み

    隅山 健太

    第66回日本人類学会大会 慶應義塾大学日吉キャンパス  2012.11 

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  86. ライブイメージングに資する4次元ヒストロジーの創生

    今西彩子, 佐藤雅也, 寺井健太, 隅山健太, 堀田一弘, 松田道行

    日本細胞生物学会大会(Web)  2017 

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  87. マウスDlx3遺伝子転写調節機構研究へのTol2システム応用の試み

    トランスポゾンに基づくゲノム・遺伝子研究  2009 

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  88. マウスDlx3遺伝子の肢芽領域における発現制御の解析

    隅山健太

    日本発生生物学会大会発表要旨集  2005.5 

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  89. ヒト特異的加速進化保存非コード配列HACNS1で正淘汰進化は起きたのか?

    第63回日本人類学会大会  2009 

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  90. ヒト特異的エンハンサーHACNS1について

    隅山 健太

    ヒト形質のゲノム発掘による新しい進化人類学の創成  2011.7 

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  91. トリプルCRISPR法による第一世代両アリル完全ノックアウトマウス作製

    隅山健太, 砂川玄志郎, 鵜飼(蓼沼)磨貴, ディミトリー ペリン, 上田泰己

    日本実験動物学会総会講演要旨集  2017.4.28 

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  92. トリプルCRISPR法による第一世代での両アリル完全ノックアウトマウス作製

    隅山健太, 砂川玄志郎, 鵜飼(蓼沼)磨貴, PERRIN Dimitri, 上田泰己

    日本遺伝学会大会プログラム・予稿集  2016.9.9 

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  93. ゲノム重複前の脊椎動物表現型を推定する新しい試み

    隅山健太

    日本進化学会大会プログラム・講演要旨集(Web)  2018.8.22 

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  94. ゲノム任意配列可視化のための高活性TALEプローブの開発

    池田一穂, 寺原陽子, 隅山健太, 岡田康志

    日本解剖学会総会・全国学術集会講演プログラム・抄録集  2016 

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  95. ほ乳類顎発生関連遺伝子Dlx3‐7クラスターの発現調節機構解析

    隅山健太

    加齢医学研究所雑誌  2004.11.20 

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  96. げっ歯類におけるRh式血液型遺伝子の進化

    北野誉, 隅山健太, 城石俊彦, 斎藤成也

    日本分子生物学会年会プログラム・講演要旨集  1998.11 

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  97. 「高速ゲノム変異マウス作製支援研究の紹介」

    隅山 健太

    理化学研究所 生命機能科学研究センター BDRスプリングコース2019  2019.3 

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  98. 「非コード領域は何のために存在する?」

    隅山 健太

    遺伝研研究集会「ビッグデータ時代の分子進化」  2015.6.27 

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  99. 「集団遺伝研究部門とゲノム編集の時代」

    隅山 健太

    木村資生先生生誕90年祝賀シンポジウム、国立遺伝学研究所、静岡県三島市  2014.11.13 

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  100. 「遺伝子改変マウスを用いた転写調節遺伝子 Dlx3-4 の機能・進化研究」

    隅山 健太

    名古屋大学 GTR セミナー  2019.1 

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  101. 「簡単で高効率なTol2トランスポゾンシステムと細胞質インジェクションによるトランスジェネシス法」

    隅山 健太

    第29回モロシヌス研究会(2015・神戸)、かんぽの宿 有馬  2015.7.4 

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KAKENHI (Grants-in-Aid for Scientific Research) 18

  1. Verification of the subfunctionalization hypothesis in paralogous genes by engrafting cis-regulatory elements

    Grant number:21H02543  2021.4 - 2024.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

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  2. Understanding of the musculoskeletal system regulated by the transcription factor Scleraxis

    Grant number:21H03107  2021.4 - 2024.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

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  3. Visualization of interglial signal transduction

    Grant number:20H05898  2020.11 - 2025.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Transformative Research Areas (A)  Grant-in-Aid for Transformative Research Areas (A)

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  4. 哺乳類鋤鼻器進化におけるDlx4遺伝子コオプション進化の解析

    2018.4 - 2021.3

    文部科学省  科学研究費補助金(基盤研究(B)) 

    隅山 健太

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  5. 細胞間コミュニケーションのライブイメージング

    Grant number:15H05949  2015 - 2019

    文部科学省  科学研究費補助金(新学術領域研究(研究領域提案型))  新学術領域研究(研究領域提案型)

    松田 道行

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  6. ゲノム編集技術応用によるシス制御因子駆動型進化メカニズムの実験検証

    Grant number:15H04408  2015 - 2017

    文部科学省  科学研究費補助金(基盤研究(B))  基盤研究(B)

    隅山 健太

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\6760000 ( Direct Cost: \5200000 、 Indirect Cost:\1560000 )

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  7. 新しいゲノム遺伝子相関を創出する脊椎動物特有の遠位エンハンサーによる進化

    Grant number:26113720  2014 - 2015

    文部科学省  科学研究費補助金(新学術領域研究(研究領域提案型))  新学術領域研究(研究領域提案型)

    隅山 健太

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\10140000 ( Direct Cost: \7800000 、 Indirect Cost:\2340000 )

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  8. 新しいゲノム遺伝子相関を創出する脊椎動物特有の遠位エンハンサーによる進化

    Grant number:24113520  2012 - 2013

    文部科学省  科学研究費補助金(新学術領域研究(研究領域提案型))  新学術領域研究(研究領域提案型)

    隅山健太

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\5720000 ( Direct Cost: \4400000 、 Indirect Cost:\1320000 )

    脊椎動物ゲノムで顕著に発達した遠位エンハンサーを、新しい遺伝子相関を形成し、新機能獲得進化を促進する仕組みとして捉え、ゲノム解析・機能解析等により検証した。【シーラカンスに見いだされた哺乳類胎盤エンハンサーの祖先配列】哺乳類においてHoxA13遺伝子は胎盤発生に必須の遺伝子である。その発現制御領域に相同な配列が、鳥類、さらにシーラカンスのHox遺伝子クラスターに発見された。興味深いことにその位置は、多くの脊椎動物ですでに失われているHoxA14遺伝子のプロモーター領域であった。このことは、遺伝子本体が失われた後もその制御領域が生き残り、新しい機能を獲得した進化の例として重要な知見である。この研究はシーラカンスゲノム論文の一部として発表した(Nature 496, 311&#8211;316. 2013)。【Dlx3/4遺伝子発現制御cis-elementのほ乳類における進化】ほ乳類特有の胎盤形成に関与すると考えられるDlx3/4遺伝子の真獣類共通に保存している胎盤エンハンサーを発見した。オポッサムの解析からエンハンサー進化の中間段階が配列比較から示唆された。進化的に保存するトランスポゾンも近傍に発見された。【 ゲノム重複によって生じたパラログ遺伝子Gsx1,Gsx2の転写制御におけるゲノム・遺伝子相関】前脳の形成に決定的に重要な役割をするパラログ遺伝子Gsx1,Gsx2は、配列相同性があり似通った組織特異性を持つエンハンサーによって制御され、さらに相互に転写を抑制制御することで相互補償的な発現を実現していると考えられる。今回このエンハンサーの機能コア配列を特定し、その配列を含む祖先的なヌタウナギのエンハンサーがマウスと同様の活性を持つことを発見した。これによりLGE形成に必要な遺伝子ネットワークがすでにヌタウナギにも存在している可能性が高まった。

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  9. Experimental verification of genomic changes which caused human-specific characters

    Grant number:23370101  2011 - 2013

    Ministry of Education, Culture, Sports, Science and Technology  Grants-in-Aid for Scientific Research(基盤研究(B))  基盤研究(B)

    Naruya SAITOU, Kenta SUMIYAMA

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    Authorship:Collaborating Investigator(s) (not designated on Grant-in-Aid)  Grant type:Competitive

    We used transgenic mice experiment for inferring function of particular DNA fragments as well as comparative genomics. Some USA researchers proposed that positive selection on short non-coding DNA created new human-specific phenotype, while Sumiyama & Saitou (2012) found same phenotype by eliminating that DNA fragment. Therefore, it is possible that phenotype emerged by loss-of-function mutations which were selectively neutral. Babarinde & Saitou (2013) conducted genome comparison and found that primate specific conserved non-coding regions are far more abundant than three other mammalian lineages (rodents, carnivores, and cetariodactyla).

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  10. 脊椎動物新奇付属器官の発生を制御するDlx3遺伝子コオプション進化機構の解明

    Grant number:22570218  2010 - 2012

    文部科学省  科学研究費補助金(基盤研究(C))  基盤研究(C)

    隅山健太

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\4680000 ( Direct Cost: \3600000 、 Indirect Cost:\1080000 )

    (1)配列解析(ERA法)による転写因子結合配列予測データベース登録配列および予備実験で配列決定した海獣類哺乳類ゲノム配列を含むすべてのゲノム配列アラインメントを用いて、ERA法により哺乳類に特異的に保存しているモチーフを抽出した。哺乳類特異的な付属器官(毛胞)組織特異性を決定している因子である可能性がある5モチーフに変異を導入したI37-1コンストラクトをデザインした。これらにつき、順次PCRを行い、制限酵素で切断し、Tol2トランスポゼースによる組み込みを可能にするベクター(pT2A-HL)にクローニングを行っている。最初に作製した1.6kbのマウスI 37-1コンストラクトについて、トランスポゼースを用いて細胞質インジェクションを行ったところ、従来法よりもはるかに効率が良く、20%以上の効率でlacZを発現する胎児個体が得られた。これらの発現パターンは以前の実験から予想された結果と良く一致していた。以上により、この系が非常に有用であることが確認された。引き続き残りのコンストラクトを作製し、Tol2を用いたトランスジェニックマウス作製系で解析する。(2)新規Dlx3-4遺伝子クラスター組織特異的エンハンサーの探索公開されているゲノムデータベースに最近になって増えてきたヒストンコードのChIP-seq解析データを用いて、脊椎動物種間で保存性が高くはないが遠位エンハンサーとし...

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  11. トランスポゾン由来進化的高度保存配列の転写調節機能獲得の進化メカニズムの解明

    Grant number:20657003  2008 - 2009

    文部科学省  科学研究費補助金(萌芽研究, 挑戦的萌芽研究)  萌芽研究, 挑戦的萌芽研究

    隅山健太

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\3300000 ( Direct Cost: \3300000 )

    前年度に引き続き、トランスポゾン由来の転写調節領域の機能解析を行うための新しいトランスジェニックマウス作成法の技術改良を行った。一般に普及している従来のトランスジェニックマウス作成法(前核微量注入法)の問題点として、効率が低いこと、ゲノムへの挿入がコンカテマーの挿入となりマルチコピーになることで組換えなどの問題が起きることがあった。ネガティブ制御配列(インシュレーターやエンハンサーブロッカーなど)になっているトランスポゾン由来の転写調節領域の機能解析を行う場合、プロモーターとの相対的な位置関係は重要な要素で、コンカテマーで挿入された場合ではその機能解析が困難である。こうした問題点を克服するため、DNA型トランスポゾンであるTol2システムを用いたトランスジェニックマウス作成方法を確立した。この方法はTol2配列で挟まれたDNAとTol2トランスポゼースmRNAをマウス受精卵の細胞質に共注入するもので、注入後の受精卵の生存率が高く、さらにゲノムへの挿入効率も非常に高いことから、トータルでの効率が従来の10倍程度高くなった。さらに、挿入は核座位につき一コピーであり、コンカデマーの問題も解消された。また導入されたレポーター遺伝子は不活性化されることなく発現することを確認した。以上の結果からこの新しいトランスジェニックマウス作成法はトランスポゾン由来の転写調節領域の機能解析はもとより...

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  12. Evolutionary analysis on regulatory mechanism of the Dlx3-7 gene cluster regarding evolution of morphological novelty.

    Grant number:18570007  2006 - 2007

    Ministry of Education, Culture, Sports, Science and Technology  Grants-in-Aid for Scientific Research(基盤研究(C))  基盤研究(C)

    Kenta SUMIYAMA

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\3910000 ( Direct Cost: \3700000 、 Indirect Cost:\210000 )

    The mammalian D1×3 and D1×7 genes are organized as a bigene cluster, and their respective expression patterns are controlled temporally and spatially by cis-elements that have been identified in the intergenic region of the cluster. Previous work showed that one of the conserved elements (137-2) was indeed a visceral arch enhancer that was able to recapitulate the nested expression pattern. We have extended these analyses to include twelve additional mammalian taxa (including a marsupial and a monotreme) in order to study evolution of the non-coding functional elements in mammals. Large-sca...

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  13. 組織特異性を決める遺伝子発現調節領域の進化メカニズム解析と人工合成による検証

    Grant number:17657079  2005 - 2006

    文部科学省  科学研究費補助金(萌芽研究)  萌芽研究

    斎藤成也, 隅山健太

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    Authorship:Collaborating Investigator(s) (not designated on Grant-in-Aid)  Grant type:Competitive

    これまでにコンピュータ解析によるゲノム中の新規機能モチーフの探索を行った。従来の方法論とはまったく異なる方法でモチーフを探索し、その結果を、進化的保存領域や機能既知の非コードゲノム領域などに基づく従来の結果と組み合わせることで新しい機能モヂュールの推定を行うことを目標としてきた。具体的には、まず最初に全ゲノム配列がわかっている生物種において、ゲノム全体を特定の長さのモチーフに切断し、そのモチーフの出現頻度を調べた。高度反復配列に含まれるモチーフや、機能の無いモチーフはゲノム中に多く見出されることが期待されるが、特定の重要な機能に結びつく配列の出現頻度は厳しく制限を受けている可能性が高い。解析の結果、期待値よりもはるかに少ないモチーフ(超低頻度モチーフ)が多数見出された。このようなゲノムの多様性は、進化的に高度な種ほど大きい傾向が見いだされた。体制の単純な生物のゲノムは超低頻度モチーフの多様性が少ない。また、超低頻度モチーフがUltra Conserved Element中に有意に高い頻度で見いだされることが判明した。このことは機能的に重要な非コード領域中の機能モチーフがゲノムの中で他にはない独自の機能を持っていることを示す。このような例に、HOXクラスター中のエンハンサーエレメントなどが見いだされ、現在この機能をトランスジェニックマウスで解析中である。また他のUltra Co...

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  14. 集団遺伝学を取り入れた種形成機構の解析

    Grant number:16057201  2004 - 2007

    文部科学省  科学研究費補助金(特定領域研究)  特定領域研究

    舘田英典, 西田睦, 隅山健太, 黒岩麻里

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    Authorship:Collaborating Investigator(s) (not designated on Grant-in-Aid)  Grant type:Competitive

    この研究では種多様化が急速に進んだと考えられる生物種群、特に東アフリカ・ビクトリア湖のシクリッド等を中心に、現存集団の遺伝的変異を解析することによって、集団のサイズや地理的構造などが、どのように種分化に寄与したかを明らかにすることを目的とする。ビクトリア湖のシクリッドについては岩場性、沿岸性の3属5種(Paralabidochromis)"rockkribensis",Lithochromis rubripinnis, L.rufus, Neochromis greenwoodi, N.rufocaudalis)でマイクロサテライト12遺伝子座の多型を調査した。沖合性二種(Haplochromis pyrrhocephalus, H.laparogramma)のデータも合わせて解析したところ、生態的に異なる岩場性・沿岸性・沖合性の種群間、及び種群内の種問に、弱いながらも階層的な遺伝的分化ができつつあることを見いだした。染色体の解析では東工大岡田グループと共同で単離したBACクローン24個のうち、20個が染色体マーカーとして使用可能なことが判明した。20個全てにおいて、マルチカラーFISH法による解析を終了させ、これら20個は18対の染色体を識別できることがわかった。一方TAARと呼ばれる化学受容体遺伝子ファミリーの進化について、9種の脊椎動物のゲノム情報を使って解析した。魚類...

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  15. マウス鰓弓内で遠近軸情報を規定するDlx3遺伝子の発現調節機構の解析

    Grant number:16027253  2004 - 2005

    文部科学省  科学研究費補助金(特定領域研究)  特定領域研究

    隅山健太

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\3900000 ( Direct Cost: \3900000 )

    1)鰓弓特異的エンハンサーI37-2エレメントについて、より詳細なデリーション解析を行った結果、250bpよりも領域を狭めた場合にはエンハンサー活性が失われることが判明した。この領域に含まれる転写因子結合配列は複数のホメオボックス因子結合配列とbHLH転写因子結合配列E-boxであったことから、これらの因子が鰓弓発現に必須の因子であることが示唆された。このほか、新たに11種のほ乳類からDlx3-7クラスター全長を含むBAC配列をスクリーニングし、配列を決定し既存の配列を含め多種間比較した。我々が用いたヒト、ヒヒ、キツネザル、マウス、ラット、ウサギ、イヌ、ウシ、ブタ、コウモリ、ヘッジホッグ、アルマジロ、オポッサムの比較では、すべての種に鰓弓特異的エンハンサーI37-2が保存しているのが確認された。ところが単孔類のカモノハシについてはこのエレメントが存在しないことがわかった。魚類ゲノムにはI37-2エレメントが存在しないことと考え合わせると、I37-2はほ乳類で進化した鰓弓由来の頭蓋形態発生に必要なエレメントである可能性が示唆される。現在この結果を投稿準備中である。2)Dlx3-7クラスターの遺伝子間領域約20kbには、I37-2以外にも複数のエンハンサー候補領域があるが、そのうちの一つI37-1からI37-3を含むDlx3遺伝子の下流約2.2kbの領域が、四肢でのDlx3遺伝子...

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  16. 哺乳類特異的形質に関わる発生調節遺伝子Dlx3-7クラスターの発現調節機構の解明

    Grant number:16770006  2004 - 2005

    文部科学省  科学研究費補助金(若手研究(B))  若手研究(B)

    隅山健太

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\3700000 ( Direct Cost: \3700000 )

    1)新たに11種のほ乳類からDlx3-7クラスター全長を含むBAC配列をスクリーニングし、配列を決定し既存の配列を含め多種間比較した。我々が用いたヒト、ヒヒ、キツネザル、マウス、ラット、ウサギ、イヌ、ウシ、ブタ、コウモリ、ヘッジホッグ、アルマジロ、オポッサムの比較では、すべての種に鰓弓特異的エンハンサーI37-2が保存しているのが確認された。ところが単孔類のカモノハシについてはこのエレメントが存在しないことがわかった。魚類ゲノムにはI37-2エレメントが存在しないことと考え合わせると、I37-2はほ乳類で進化した鰓弓由来の頭蓋形態発生に必要なエレメントである可能性が示唆される。現在この結果を投稿準備中である。2)Dlx3-7クラスターの遺伝子間領域約20kbには、I37-2以外にも複数のエンハンサー候補領域があるが、そのうちの一つI37-1からI37-3を含むDlx3遺伝子の下流約2.2kbの領域が、四肢でのDlx3遺伝子の発現を制御する領域であり、このエレメント中には指間領域およびAER両方の発現制御領域が含まれていることを明らかにした。興味深いことに、Dlx3下流のこの領域は両生類では四肢のエンハンサーではなく、別のDlx3遺伝子上流の四肢エンハンサーが存在している。このことから脊椎動物の進化の過程で同じ活性を有するエンハンサーエレメントの位置はダイナミックに変化している...

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  17. 霊長類免疫グロブリンCα遺伝子ヒンジ領域における正淘汰進化の研究

    1996 - 1998

    日本学術振興会  特別研究員奨励費 国内 人類学(含生理人類学) 

    隅山 健太

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  18. Molecular evolution of cis-regulatory elements in developmental control.

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Industrial property rights 5

  1. 遺伝子のノックアウト方法

    上田 泰己, 砂川 玄志郎, 隅山 健太, 鵜飼 磨貴, ペリン ディミトリ

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    Applicant:国立研究開発法人理化学研究所

    Application no:JP2015086259  Date applied:2015.12

    Announcement no:WO2016-104716  Date announced:2016.6

    J-GLOBAL

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  2. 蛍光共鳴エネルギー移動の原理に基づく一分子型FRETバイオセンサーのリンカー

    松田 道行, 小松 直貴, 青木 一洋, 上岡 裕治, 幸長 弘子, 稲岡 芳恵, 櫻井 敦朗, 清川 悦子, 隅山 健太

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    Applicant:LSIPファンド運営合同会社

    Application no:JP2011071891  Date applied:2011.9

    Announcement no:WO2012-043477  Date announced:2012.4

    J-GLOBAL

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  3. 蛍光共鳴エネルギー移動の原理に基づく一分子型FRETバイオセンサーのリンカー

    松田 道行, 小松 直貴, 青木 一洋, 上岡 裕治, 幸長 弘子, 稲岡 芳恵, 櫻井 敦朗, 清川 悦子, 隅山 健太

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    Applicant:国立大学法人京都大学, LSIPファンド運営合同会社

    Application no:特願2012-536438  Date applied:2011.9

    Patent/Registration no:特許第5802674号  Date issued:2015.9

    J-GLOBAL

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  4. LINKER FOR UNIMOLECULAR FRET BIOSENSOR BASED ON PRINCIPLE OF FLUORESCENCE RESONANCE ENERGY TRANSFER

    MATSUDA, Michiyuki KOMATSU, Naoki AOKI, Kazuhiro KAMIOKA, Yuuji YUKINAGA, Hiroko INAOKA, Yoshie SAKURAI, Aturou KIYOKAWA, Etuko SUMIYAMA, Kenta

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    Application no:特願2010-215738  Date applied:2010.9

    Announcement no:WO 2012/043477 

    Patent/Registration no:F120006680 

    [Problem] To provide a linker for a unimolecular FRET biosensor, as well as a unimolecular FRET biosensor and such generally containing a linker, which enable the measurement of non-invasive serine-threonine protein kinase activity, tyrosine kinase activity, and small GTP-binding protein activity, and are based on the principle of fluorescence resonance energy transfer. [Solution] Provided is: a linker that is a polypeptide containing between 52 and 400 amino acid residues, with at least 95% of the total number of amino acid residues comprising glycine, serine, threonine, and alanine, and which contains 35-65% of glycine, 10-40% of serine and/or threonine, and 10-40% of alanine; unimolecular FRET biosensors mostly containing linkers; a transformed cell which holds an expression vector containing a g

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  5. Efficient cis-element discovery method using multiple sequence comparisons based on evolutionary relationships.

    Ruddle, Frank H. (Ne, Haven, CT, Sumiyama, Kenta (New, Haven, CT, Kim, Chang-Bae (New, Haven, CT

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    Application no:United States Patent 6,917,883  Date applied:2005.7

    United States Patent 6,917,883

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Teaching Experience (Off-campus) 10

  1. 発生生物学2(英語、分担)

    総合研究大学院大学遺伝学専攻)

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  2. 生命科学論文演習(集団遺伝学セミナー、英語)

    総合研究大学院大学遺伝学専攻)

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  3. 生命科学論文演習(形態形成ジャーナルクラブ、英語)

    総合研究大学院大学遺伝学専攻)

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  4. 生命科学論文演習(分子進化セミナー、英語)

    総合研究大学院大学遺伝学専攻)

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  5. 生命科学論文演習(マウス発生学セミナー、英語)

    総合研究大学院大学遺伝学専攻)

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  6. 生命科学実験演習

    総合研究大学院大学遺伝学専攻)

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  7. 理研QBiCスプリングコース講義「高速ゲノム変異マウス作製研究」

    理化学研究所・生命システム研究センター)

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  8. 特別集中講義・QBiCで展開する先端生命科学研究(英語、分担)

    大阪大学生命機能研究科)

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  9. Evolutionary Genomics (集中講義、英語)

    台湾成功大学)

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  10. 集中レクチャー【ゲノム・発生・進化】発生調節遺伝子の発現制御と発生進化

    理化学研究所 生命機能科学研究センター 連携大学院)

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