2022/04/12 更新

写真a

ヒビ マサヒコ
日比 正彦
HIBI, Masahiko
所属
大学院理学研究科 理学専攻 生命理学 教授
大学院担当
大学院理学研究科
学部担当
理学部 生命理学科
職名
教授
連絡先
メールアドレス
外部リンク

学位 1

  1. 博士(医学) ( 1992年3月   大阪大学 ) 

研究キーワード 6

  1. ゼブラフィッシュ

  2. 神経発生

  3. 神経回路

  4. 小脳

  5. 体軸形成

  6. メダカ

研究分野 2

  1. その他 / その他  / 発生生物学

  2. その他 / その他  / 神経科学一般

現在の研究課題とSDGs 2

  1. 小脳神経回路の機能解析

  2. 小脳神経回路形成の分子機構

経歴 6

  1. 名古屋大学   大学院理学研究科   教授

    2019年4月 - 現在

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    国名:日本国

  2. 名古屋大学   生物機能開発利用研究センター   教授

    2009年4月 - 2009年3月

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    国名:日本国

  3. 理化学研究所   発生・再生科学総合研究センター・チームリーダー   教授

    2001年4月 - 2009年3月

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    国名:日本国

  4. 大阪大学   医学系研究科・助教授   准教授

    1999年4月 - 2001年3月

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    国名:日本国

  5. 大阪大学   医学部   助手

    1995年1月 - 1999年3月

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    国名:日本国

  6. カリフォルニア大学サンディエゴ校   薬理学部門   研究員

    1992年4月 - 1995年1月

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    国名:アメリカ合衆国

▼全件表示

学歴 2

  1. 大阪大学   医学系研究科   免疫学

    1988年4月 - 1992年3月

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    国名: 日本国

  2. 広島大学   医学部   医学科

    1982年4月 - 1988年3月

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    国名: 日本国

所属学協会 3

  1. 日本発生生物学会

  2. 日本神経科学学会

  3. 日本分子生物学会

受賞 1

  1. 日本癌学会奨励賞

    2000年  

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    受賞国:日本国

 

論文 44

  1. A point-mutation in the C-domain of CMP-sialic acid synthetase leads to lethality of medaka due to protein insolubility

    Wu Di, Arakawa Hiromu, Fujita Akiko, Hashimoto Hisashi, Hibi Masahiko, Naruse Kiyoshi, Kamei Yasuhiro, Sato Chihiro, Kitajima Ken

    SCIENTIFIC REPORTS   11 巻 ( 1 ) 頁: 23211   2021年12月

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    記述言語:日本語   出版者・発行元:Scientific Reports  

    Vertebrate CMP-sialic acid synthetase (CSS), which catalyzes the synthesis of CMP-sialic acid (CMP-Sia), consists of a 28 kDa-N-domain and a 20 kDa-C-domain. The N-domain is known to be a catalytic domain; however, the significance of the C-domain still remains unknown. To elucidate the function of the C-domain at the organism level, we screened the medaka TILLING library and obtained medaka with non-synonymous mutations (t911a), or single amino acid substitutions of CSS, L304Q, in the C-domain. Prominently, most L304Q medaka was lethal within 19 days post-fertilization (dpf). L304Q young fry displayed free Sia accumulation, and impairment of sialylation, up to 8 dpf. At 8 dpf, a marked abnormality in ventricular contraction and skeletal myogenesis was observed. To gain insight into the mechanism of L304Q-induced abnormalities, L304Q was biochemically characterized. Although bacterially expressed soluble L304Q and WT showed the similar Vmax/Km values, very few soluble L304Q was detected when expressed in CHO cells in sharp contrast to the WT. Additionally, the thermostability of various mutations of L304 greatly decreased, except for WT and L304I. These results suggest that L304 is important for the stability of CSS, and that an appropriate level of expression of soluble CSS is significant for animal survival.

    DOI: 10.1038/s41598-021-01715-3

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  2. Contribution of sox9b to pigment cell formation in medaka fish

    Tsunogai Yuri, Miyadai Motohiro, Nagao Yusuke, Sugiwaka Keisuke, Kelsh Robert N., Hibi Masahiko, Hashimoto Hisashi

    DEVELOPMENT GROWTH & DIFFERENTIATION   63 巻 ( 9 ) 頁: 516 - 522   2021年12月

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    記述言語:日本語   出版者・発行元:Development Growth and Differentiation  

    SoxE-type transcription factors, Sox10 and Sox9, are key regulators of the development of neural crest cells. Sox10 specifies pigment cell, glial, and neuronal lineages, whereas Sox9 is reportedly closely associated with skeletogenic lineages in the head, but its involvement in pigment cell formation has not been investigated genetically. Thus, it is not fully understood whether or how distinctly these genes as well as their paralogs in teleosts are subfunctionalized. We have previously shown using the medaka fish Oryzias latipes that pigment cell formation is severely affected by the loss of sox10a, yet unaffected by the loss of sox10b. Here we aimed to determine whether Sox9 is involved in the specification of pigment cell lineage. The sox9b homozygous mutation did not affect pigment cell formation, despite lethality at the early larval stages. By using sox10a, sox10b, and sox9b mutations, compound mutants were established for the sox9b and sox10 genes and pigment cell phenotypes were analyzed. Simultaneous loss of sox9b and sox10a resulted in the complete absence of melanophores and xanthophores from hatchlings and severely defective iridophore formation, as has been previously shown for sox10a−/−; sox10b−/− double mutants, indicating that Sox9b as well as Sox10b functions redundantly with Sox10a in pigment cell development. Notably, leucophores were present in sox9b−/−; sox10a−/− and sox10a−/−; sox10b−/− double mutants, but their numbers were significantly reduced in the sox9b−/−; sox10a−/− mutants. These findings highlight that Sox9b is involved in pigment cell formation, and plays a more critical role in leucophore development than Sox10b.

    DOI: 10.1111/dgd.12760

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  3. Maintenance of quiescent oocytes by noradrenergic signals

    Kim Jeongho, Hyun Moonjung, Hibi Masahiko, You Young-Jai

    NATURE COMMUNICATIONS   12 巻 ( 1 ) 頁: 6925   2021年11月

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    記述言語:日本語   出版者・発行元:Nature Communications  

    All females adopt an evolutionary conserved reproduction strategy; under unfavorable conditions such as scarcity of food or mates, oocytes remain quiescent. However, the signals to maintain oocyte quiescence are largely unknown. Here, we report that in four different species – Caenorhabditis elegans, Caenorhabditis remanei, Drosophila melanogaster, and Danio rerio – octopamine and norepinephrine play an essential role in maintaining oocyte quiescence. In the absence of mates, the oocytes of Caenorhabditis mutants lacking octopamine signaling fail to remain quiescent, but continue to divide and become polyploid. Upon starvation, the egg chambers of D. melanogaster mutants lacking octopamine signaling fail to remain at the previtellogenic stage, but grow to full-grown egg chambers. Upon starvation, D. rerio lacking norepinephrine fails to maintain a quiescent primordial follicle and activates an excessive number of primordial follicles. Our study reveals an evolutionarily conserved function of the noradrenergic signal in maintaining quiescent oocytes.

    DOI: 10.1038/s41467-021-26945-x

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  4. Morphological analysis of the cerebellum and its efferent system in a basal actinopterygian fish, Polypterus senegalus

    Ikenaga Takanori, Shimomai Rinko, Hagio Hanako, Kimura Satoru, Matsumoto Kazumasa, Kato Dai-ichiro, Uesugi Kentaro, Takeuchi Akihisa, Yamamoto Naoyuki, Hibi Masahiko

    JOURNAL OF COMPARATIVE NEUROLOGY     2021年11月

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    記述言語:日本語   出版者・発行元:Journal of Comparative Neurology  

    Although all vertebrate cerebella contain granule cells, Purkinje cells, and efferent neurons, the cellular arrangement and neural circuitry are highly diverse. In amniotes, cerebellar efferent neurons form clusters, deep cerebellar nuclei, lie deep in the cerebellum, and receive synaptic inputs from Purkinje cells but not granule cells. However, in the cerebellum of teleosts, the efferent neurons, called eurydendroid cells, lie near the cell bodies of Purkinje cells and receive inputs both from axons of Purkinje cells and granule cell parallel fibers. It is largely unknown how the cerebellar structure evolved in ray-finned fish (actinopterygians). To address this issue, we analyzed the cerebellum of a bichir Polypterus senegalus, one of the most basal actinopterygians. We found that the cell bodies of Purkinje cells are not aligned in a layer; incoming climbing fibers terminate mainly on the basal portion of Purkinje cells, revealing that the Polypterus cerebellum has unique features among vertebrate cerebella. Retrograde labeling and marker analyses of the efferent neurons revealed that their cell bodies lie in restricted granular areas but not as deep cerebellar nuclei in the cerebellar white matter. The efferent neurons have long dendrites like eurydendroid cells, although they do not reach the molecular layer. Our findings suggest that the efferent system of the bichir cerebellum has intermediate features between teleosts and amniote vertebrates, and provides a model to understand the basis generating diversity in actinopterygian cerebella.

    DOI: 10.1002/cne.25271

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  5. Cfdp1 controls the cell cycle and neural differentiation in the zebrafish cerebellum and retina

    Itoh Tsubasa, Inoue Shinsuke, Sun Xiaoding, Kusuda Ryo, Hibi Masahiko, Shimizu Takashi

    DEVELOPMENTAL DYNAMICS   250 巻 ( 11 ) 頁: 1618 - 1633   2021年11月

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    記述言語:日本語   出版者・発行元:Developmental Dynamics  

    Background: Although the cell cycle and cell differentiation should be coordinately regulated to generate a variety of neurons in the brain, the molecules that are involved in this coordination still remain largely unknown. In this study, we analyzed the roles of a nuclear protein Cfdp1, which is thought to be involved in chromatin remodeling, in zebrafish neurogenesis. Results: Zebrafish cfdp1 mutants maintained the progenitors of granule cells (GCs) in the cerebellum, but showed defects in their differentiation to GCs. cfdp1 mutants showed an increase in phospho-histone 3 (pH 3)-positive cells and apoptotic cells, as well as a delayed cell cycle transition from the G2 to the M phase in the cerebellum. The inhibition of tp53 prevented apoptosis but not GC differentiation in the cfdp1 mutant cerebellum. A similar increase in apoptotic cells and pH 3-positive cells, and defective cell differentiation, were observed in the cfdp1 mutant retina. Although mitotic spindles formed, mitosis was blocked before anaphase in both the cerebellum and retina of cfdp1 mutant larvae. Furthermore, expression of the G2/mitotic-specific cyclin B1 gene increased in the cfdp1 mutant cerebellum. Conclusions: Our findings suggest that Cfdp1 regulates the cell cycle of neural progenitors, thereby promoting neural differentiation in the brain.

    DOI: 10.1002/dvdy.371

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  6. 特集 小脳研究の未来 Ⅰ.発生発達 ゼブラフィッシュ小脳神経回路の発生と機能

    清水 貴史, 日比 正彦

    生体の科学   72 巻 ( 1 ) 頁: 3 - 8   2021年2月

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    出版者・発行元:株式会社医学書院  

    DOI: 10.11477/mf.2425201301

    CiNii Research

  7. Involvement of cerebellar neural circuits in active avoidance conditioning in zebrafish

    Koyama Wataru, Hosomi Ryo, Matsuda Koji, Kawakami Koichi, Hibi Masahiko, Shimizu Takashi

    ENEURO   8 巻 ( 3 )   2021年

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    記述言語:日本語   出版者・発行元:eNeuro  

    When animals repeatedly receive a combination of neutral conditional stimulus (CS) and aversive unconditional stimulus (US), they learn the relationship between CS and US, and show conditioned fear responses after CS. They show passive responses such as freezing or panic movements (classical or Pavlovian fear conditioning), or active behavioral responses to avoid aversive stimuli (active avoidance). Previous studies suggested the roles of the cerebellum in classical fear conditioning but it remains elusive whether the cerebellum is involved in active avoidance conditioning. In this study, we analyzed the roles of cerebellar neural circuits during active avoidance in adult zebrafish. When pairs of CS (light) and US (electric shock) were administered to wild-type zebrafish, about half of them displayed active avoidance. The expression of botulinum toxin, which inhibits the release of neurotransmitters, in cerebellar granule cells (GCs) or Purkinje cells (PCs) did not affect condition-ing-independent swimming behaviors, but did inhibit active avoidance conditioning. Nitroreductase (NTR)-mediated ablation of PCs in adult zebrafish also impaired active avoidance. Furthermore, the inhibited transmission of GCs or PCs resulted in reduced fear-conditioned Pavlovian fear responses. Our findings suggest that the zebrafish cerebellum plays an active role in active avoidance conditioning.

    DOI: 10.1523/ENEURO.0507-20.2021

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

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

    DEVELOPMENT   147 巻 ( 19 )   2020年10月

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    記述言語:日本語   出版者・発行元:Development (Cambridge, England)  

    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.

    DOI: 10.1242/dev.190603

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  9. Functionally distinct Purkinje cell types show temporal precision in encoding locomotion

    Chang Weipang, Pedroni Andrea, Hohendorf Victoria, Giacomello Stefania, Hibi Masahiko, Koester Reinhard W., Ampatzis Konstantinos

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   117 巻 ( 29 ) 頁: 17330 - 17337   2020年7月

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    記述言語:日本語   出版者・発行元:Proceedings of the National Academy of Sciences of the United States of America  

    Purkinje cells, the principal neurons of cerebellar computations, are believed to comprise a uniform neuronal population of cells, each with similar functional properties. Here, we show an undiscovered heterogeneity of adult zebrafish Purkinje cells, revealing the existence of anatomically and functionally distinct cell types. Dual patch-clamp recordings showed that the cerebellar circuit contains all Purkinje cell types that cross-communicate extensively using chemical and electrical synapses. Further activation of spinal central pattern generators (CPGs) revealed unique phase-locked activity from each Purkinje cell type during the locomotor cycle. Thus, we show intricately organized Purkinje cell networks in the adult zebrafish cerebellum that encode the locomotion rhythm differentially, and we suggest that these organizational properties may also apply to other cerebellar functions.

    DOI: 10.1073/pnas.2005633117

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  10. Molecular Properties of New Enzyme Rhodopsins with Phosphodiesterase Activity

    Sugiura Masahiro, Tsunoda Satoshi P., Hibi Masahiko, Kandori Hideki

    ACS OMEGA   5 巻 ( 18 ) 頁: 10602 - 10609   2020年5月

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    記述言語:日本語   出版者・発行元:ACS Omega  

    The choanoflagellate Salpingoeca rosetta contains a chimeric rhodopsin protein composed of an N-terminal rhodopsin (Rh) domain and a C-terminal cyclic nucleotide phosphodiesterase (PDE) domain. The Rh-PDE enzyme (SrRh-PDE), which decreases the concentrations of cyclic nucleotides such as cGMP and cAMP in light, is a useful tool in optogenetics. Recently, eight additional Rh-PDE enzymes were found in choanoflagellate species, four from Choanoeca flexa and the other four from other species. In this paper, we studied the molecular properties of these new Rh-PDEs, which were compared with SrRh-PDE. Upon expression in HEK293 cells, four Rh-PDE proteins, including CfRh-PDE2 and CfRh-PDE3, exhibited no PDE activity when assessed by in-cell measurements and in vitro HPLC analysis. On the other hand, CfRh-PDE1 showed light-dependent PDE activity toward cGMP, which absorbed maximally at 491 nm. Therefore, CfRh-PDE1 is presumably responsible for colony inversion in C. flexa by absorbing blue-green light. The molecular properties of MrRh-PDE were similar to those of SrRh-PDE, although the λmax of MrRh-PDE (516 nm) was considerably red-shifted from that of SrRh-PDE (492 nm). One Rh-PDE, AsRh-PDE, did not contain the retinal-binding Lys at TM7 and showed cAMP-specific PDE activity both in the dark and light. These results provide mechanistic insight into rhodopsin-mediated, light-dependent regulation of second-messenger levels in eukaryotic microbes.

    DOI: 10.1021/acsomega.0c01113

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  11. Role of Reelin in cell positioning in the cerebellum and the cerebellum-like structure in zebrafish

    Nimura Takayuki, Itoh Tsubasa, Hagio Hanako, Hayashi Takuto, Di Donato Vincenzo, Takeuchi Miki, Itoh Takeaki, Inoguchi Fuduki, Sato Yoshikatsu, Yamamoto Naoyuki, Katsuyama Yu, Del Bene Filippo, Shimizu Takashi, Hibi Masahiko

    DEVELOPMENTAL BIOLOGY   455 巻 ( 2 ) 頁: 393 - 408   2019年11月

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    記述言語:日本語   出版者・発行元:Developmental Biology  

    The cerebellum and the cerebellum-like structure in the mesencephalic tectum in zebrafish contain multiple cell types, including principal cells (i.e., Purkinje cells and type I neurons) and granule cells, that form neural circuits in which the principal cells receive and integrate inputs from granule cells and other neurons. It is largely unknown how these cells are positioned and how neural circuits form. While Reelin signaling is known to play an important role in cell positioning in the mammalian brain, its role in the formation of other vertebrate brains remains elusive. Here we found that zebrafish with mutations in Reelin or in the Reelin-signaling molecules Vldlr or Dab1a exhibited ectopic Purkinje cells, eurydendroid cells (projection neurons), and Bergmann glial cells in the cerebellum, and ectopic type I neurons in the tectum. The ectopic Purkinje cells and type I neurons received aberrant afferent fibers in these mutants. In wild-type zebrafish, reelin transcripts were detected in the internal granule cell layer, while Reelin protein was localized to the superficial layer of the cerebellum and the tectum. Laser ablation of the granule cell axons perturbed the localization of Reelin, and the mutation of both kif5aa and kif5ba, which encode major kinesin I components in the granule cells, disrupted the elongation of granule cell axons and the Reelin distribution. Our findings suggest that in zebrafish, (1) Reelin is transported from the granule cell soma to the superficial layer by axonal transport; (2) Reelin controls the migration of neurons and glial cells from the ventricular zone; and (3) Purkinje cells and type I neurons attract afferent axons during the formation of the cerebellum and the cerebellum-like structure.

    DOI: 10.1016/j.ydbio.2019.07.010

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  12. Tracing of Afferent Connections in the Zebrafish Cerebellum Using Recombinant Rabies Virus

    Dohaku Ryuji, Yamaguchi Masahiro, Yamamoto Naoyuki, Shimizu Takashi, Osakada Fumitaka, Hibi Masahiko

    FRONTIERS IN NEURAL CIRCUITS   13 巻   頁: 30   2019年4月

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    記述言語:日本語   出版者・発行元:Frontiers in Neural Circuits  

    The cerebellum is involved in some forms of motor coordination and learning, and in cognitive and emotional functions. To elucidate the functions of the cerebellum, it is important to unravel the detailed connections of the cerebellar neurons. Although the cerebellar neural circuit structure is generally conserved among vertebrates, it is not clear whether the cerebellum receives and processes the same or similar information in different vertebrate species. Here, we performed monosynaptic retrograde tracing with recombinant rabies viruses (RV) to identify the afferent connections of the zebrafish cerebellar neurons. We used a G-deleted RV that expressed GFP. The virus was also pseudotyped with EnvA, an envelope protein of avian sarcoma and leucosis virus (ALSV-A). For the specific infection of cerebellar neurons, we expressed the RV glycoprotein (G) gene and the envelope protein TVA, which is the receptor for EnvA, in Purkinje cells (PCs) or granule cells (GCs), using the promoter for aldolase Ca (aldoca) or cerebellin 12 (cbln12), respectively. When the virus infected PCs in the aldoca line, GFP was detected in the PCs’ presynaptic neurons, including GCs and neurons in the inferior olivary nuclei (IOs), which send climbing fibers (CFs). These observations validated the RV tracing method in zebrafish. When the virus infected GCs in the cbln12 line, GFP was again detected in their presynaptic neurons, including neurons in the pretectal nuclei, the nucleus lateralis valvulae (NLV), the central gray (CG), the medial octavolateralis nucleus (MON), and the descending octaval nucleus (DON). GFP was not observed in these neurons when the virus infected PCs in the aldoca line. These precerebellar neurons generally agree with those reported for other teleost species and are at least partly conserved with those in mammals. Our results demonstrate that the RV system can be used for connectome analyses in zebrafish, and provide fundamental information about the cerebellar neural circuits, which will be valuable for elucidating the functions of cerebellar neural circuits in zebrafish.

    DOI: 10.3389/fncir.2019.00030

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  13. Syntaphilin-Mediated Docking of Mitochondria at the Growth Cone Is Dispensable or Axon Elongation In Vivo

    Verreet Tine, Weaver Cory J., Hino Hiromu, Hibi Masahiko, Poulain Fabienne E.

    ENEURO   6 巻 ( 5 )   2019年

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    記述言語:日本語   出版者・発行元:eNeuro  

    Mitochondria are abundantly detected at the growth cone, the dynamic distal tip of developing axons that directs growth and guidance. It is, however, poorly understood how mitochondrial dynamics relate to growth cone behavior in vivo, and which mechanisms are responsible for anchoring mitochondria at the growth cone during axon pathfinding. Here, we show that in retinal axons elongating along the optic tract in zebrafish, mitochondria accumulate in the central area of the growth cone and are occasionally observed in filopodia extending from the growth cone periphery. Mitochondrial behavior at the growth cone in vivo is dynamic, with mitochondrial positioning and anterograde transport strongly correlating with growth cone behavior and axon outgrowth. Using novel zebrafish mutant lines that lack the mitochondrial anchoring proteins Syntaphilin a and b, we further show that Syntaphilins contribute to mitochondrial immobilization at the growth cone. Syntaphilins are, however, not required for proper growth cone morphology and axon growth in vivo, indicating that Syntaphilin-mediated anchoring of mitochondria at the growth cone plays only a minor role in elongating axons.

    DOI: 10.1523/ENEURO.0026-19.2019

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  14. Color opponency with a single kind of bistable opsin in the zebrafish pineal organ

    Wada Seiji, Shen Baoguo, Kawano-Yamashita Emi, Nagata Takashi, Hibi Masahiko, Tamotsu Satoshi, Koyanagi Mitsumasa, Terakita Akihisa

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   115 巻 ( 44 ) 頁: 11310 - 11315   2018年10月

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    記述言語:日本語   出版者・発行元:Proceedings of the National Academy of Sciences of the United States of America  

    Lower vertebrate pineal organs discriminate UV and visible light. Such color discrimination is typically considered to arise from antagonism between two or more spectrally distinct opsins, as, e.g., human cone-based color vision relies on antagonistic relationships between signals produced by red-, green-, and blue-cone opsins. Photosensitive pineal organs contain a bistable opsin (parapinopsin) that forms a signaling-active photoproduct upon UV exposure that may itself be returned to the signaling-inactive "dark" state by longer-wavelength light. Here we show the spectrally distinct parapinopsin states (with antagonistic impacts on signaling) allow this opsin alone to provide the color sensitivity of this organ. By using calcium imaging, we show that single zebrafish pineal photoreceptors held under a background light show responses of opposite signs to UV and visible light. Both such responses are deficient in zebrafish lacking parapinopsin. Expressing a UV-sensitive cone opsin in place of parapinopsin recovers UV responses but not color opponency. Changes in the spectral composition of white light toward enhanced UV or visible wavelengths respectively increased vs. decreased calcium signal in parapinopsinsufficient but not parapinopsin-deficient photoreceptors. These data reveal color opponency from a single kind of bistable opsin establishing an equilibrium-like mixture of the two states with different signaling abilities whose fractional concentrations are defined by the spectral composition of incident light. As vertebrate visual color opsins evolved from a bistable opsin, these findings suggest that color opponency involving a single kind of bistable opsinmight have been a prototype of vertebrate color opponency.

    DOI: 10.1073/pnas.1802592115

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  15. Multiple zebrafish atoh1 genes specify a diversity of neuronal types in the zebrafish cerebellum

    Kidwell Chelsea U., Su Chen-Ying, Hibi Masahiko, Moens Cecilia B.

    DEVELOPMENTAL BIOLOGY   438 巻 ( 1 ) 頁: 44 - 56   2018年6月

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    記述言語:日本語   出版者・発行元:Developmental Biology  

    A single Atoh1 basic-helix-loop-helix transcription factor specifies multiple neuron types in the mammalian cerebellum and anterior hindbrain. The zebrafish genome encodes three paralagous atoh1 genes whose functions in cerebellum and anterior hindbrain development we explore here. With use of a transgenic reporter, we report that zebrafish atoh1c-expressing cells are organized in two distinct domains that are separated both by space and developmental time. An early isthmic expression domain gives rise to an extracerebellar population in rhombomere 1 and an upper rhombic lip domain gives rise to granule cell progenitors that migrate to populate all four granule cell territories of the fish cerebellum. Using genetic mutants we find that of the three zebrafish atoh1 paralogs, atoh1c and atoh1a are required for the full complement of granule neurons. Surprisingly, the two genes are expressed in non-overlapping granule cell progenitor populations, indicating that fish use duplicate atoh1 genes to generate granule cell diversity that is not detected in mammals. Finally, live imaging of granule cell migration in wildtype and atoh1c mutant embryos reveals that while atoh1c is not required for granule cell specification per se, it is required for granule cells to delaminate and migrate away from the rhombic lip.

    DOI: 10.1016/j.ydbio.2018.03.004

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  16. Madagascar ground gecko genome analysis characterizes asymmetric fates of duplicated genes

    Hara Yuichiro, Takeuchi Miki, Kageyama Yuka, Tatsumi Kaori, Hibi Masahiko, Kiyonari Hiroshi, Kuraku Shigehiro

    BMC BIOLOGY   16 巻 ( 1 ) 頁: 40   2018年4月

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    記述言語:日本語   出版者・発行元:BMC Biology  

    Background: Conventionally, comparison among amniotes - birds, mammals, and reptiles - has often been approached through analyses of mammals and, for comparison, birds. However, birds are morphologically and physiologically derived and, moreover, some parts of their genomes are recognized as difficult to sequence and/or assemble and are thus missing in genome assemblies. Therefore, sequencing the genomes of reptiles would aid comparative studies on amniotes by providing more comprehensive coverage to help understand the molecular mechanisms underpinning evolutionary changes. Results: Herein, we present the whole genome sequences of the Madagascar ground gecko (Paroedura picta), a promising study system especially in developmental biology, and used it to identify changes in gene repertoire across amniotes. The genome-wide analysis of the Madagascar ground gecko allowed us to reconstruct a comprehensive set of gene phylogenies comprising 13,043 ortholog groups from diverse amniotes. Our study revealed 469 genes retained by some reptiles but absent from available genome-wide sequence data of both mammals and birds. Importantly, these genes, herein collectively designated as 'elusive' genes, exhibited high nucleotide substitution rates and uneven intra-genomic distribution. Furthermore, the genomic regions flanking these elusive genes exhibited distinct characteristics that tended to be associated with increased gene density, repeat element density, and GC content. Conclusion: This highly continuous and nearly complete genome assembly of the Madagascar ground gecko will facilitate the use of this species as an experimental animal in diverse fields of biology. Gene repertoire comparisons across amniotes further demonstrated that the fate of a duplicated gene can be affected by the intrinsic properties of its genomic location, which can persist for hundreds of millions of years.

    DOI: 10.1186/s12915-018-0509-4

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  17. Distinct interactions of Sox5 and Sox10 in fate specification of pigment cells in medaka and zebrafish

    Nagao Yusuke, Takada Hiroyuki, Miyadai Motohiro, Adachi Tomoko, Seki Ryoko, Kamei Yasuhiro, Hara Ikuyo, Taniguchi Yoshihito, Naruse Kiyoshi, Hibi Masahiko, Kelsh Robert N., Hashimoto Hisashi

    PLOS GENETICS   14 巻 ( 4 ) 頁: e1007260   2018年4月

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    記述言語:日本語   出版者・発行元:PLoS genetics  

    Mechanisms generating diverse cell types from multipotent progenitors are fundamental for normal development. Pigment cells are derived from multipotent neural crest cells and their diversity in teleosts provides an excellent model for studying mechanisms controlling fate specification of distinct cell types. Zebrafish have three types of pigment cells (melanocytes, iridophores and xanthophores) while medaka have four (three shared with zebrafish, plus leucophores), raising questions about how conserved mechanisms of fate specification of each pigment cell type are in these fish. We have previously shown that the Sry-related transcription factor Sox10 is crucial for fate specification of pigment cells in zebrafish, and that Sox5 promotes xanthophores and represses leucophores in a shared xanthophore/leucophore progenitor in medaka. Employing TILLING, TALEN and CRISPR/Cas9 technologies, we generated medaka and zebrafish sox5 and sox10 mutants and conducted comparative analyses of their compound mutant phenotypes. We show that specification of all pigment cells, except leucophores, is dependent on Sox10. Loss of Sox5 in Sox10-defective fish partially rescued the formation of all pigment cells in zebrafish, and melanocytes and iridophores in medaka, suggesting that Sox5 represses Sox10-dependent formation of these pigment cells, similar to their interaction in mammalian melanocyte specification. In contrast, in medaka, loss of Sox10 acts cooperatively with Sox5, enhancing both xanthophore reduction and leucophore increase in sox5 mutants. Misexpression of Sox5 in the xanthophore/leucophore progenitors increased xanthophores and reduced leucophores in medaka. Thus, the mode of Sox5 function in xanthophore specification differs between medaka (promoting) and zebrafish (repressing), which is also the case in adult fish. Our findings reveal surprising diversity in even the mode of the interactions between Sox5 and Sox10 governing specification of pigment cell types in medaka and zebrafish, and suggest that this is related to the evolution of a fourth pigment cell type.

    DOI: 10.1371/journal.pgen.1007260

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  18. Roles of maternal wnt8a transcripts in axis formation in zebrafish

    Hino Hiromu, Nakanishi Akiko, Seki Ryoko, Aoki Tsubasa, Yamaha Etsuro, Kawahara Atsuo, Shimizu Takashi, Hibi Masahiko

    DEVELOPMENTAL BIOLOGY   434 巻 ( 1 ) 頁: 96 - 107   2018年2月

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    記述言語:日本語   出版者・発行元:Developmental Biology  

    In early zebrafish development, the program for dorsal axis formation begins soon after fertilization. Previous studies suggested that dorsal determinants (DDs) localize to the vegetal pole, and are transported to the dorsal blastomeres in a microtubule-dependent manner. The DDs activate the canonical Wnt pathway and induce dorsal-specific genes that are required for dorsal axis formation. Among wnt-family genes, only the wnt8a mRNA is reported to localize to the vegetal pole in oocytes and to induce the dorsal axis, suggesting that Wnt8a is a candidate DD. Here, to reveal the roles of maternal wnt8a, we generated wnt8a mutants by transcription activator-like effector nucleases (TALENs), and established zygotic, maternal, and maternal zygotic wnt8a mutants by germ-line replacement. Zebrafish wnt8a has two open reading frames (ORF1 and ORF2) that are tandemly located in the genome. Although the zygotic ORF1 or ORF2 wnt8a mutants showed little or no axis-formation defects, the ORF1/2 compound mutants showed antero-dorsalized phenotypes, indicating that ORF1 and ORF2 have redundant roles in ventrolateral and posterior tissue formation. Unexpectedly, the maternal wnt8a ORF1/2 mutants showed no axis-formation defects. The maternal-zygotic wnt8a ORF1/2 mutants showed more severe antero-dorsalized phenotypes than the zygotic mutants. These results indicated that maternal wnt8a is dispensable for the initial dorsal determination, but cooperates with zygotic wnt8a for ventrolateral and posterior tissue formation. Finally, we re-examined the maternal wnt genes and found that Wnt6a is an alternative candidate DD.

    DOI: 10.1016/j.ydbio.2017.11.016

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  19. Gene expression profiling of granule cells and Purkinje cells in the zebrafish cerebellum 査読有り

    Takeuchi Miki, Yamaguchi Shingo, Sakakibara Yoshimasa, Hayashi Takuto, Matsuda Koji, Hara Yuichiro, Tanegashima Chiharu, Shimizu Takashi, Kuraku Shigehiro, Hibi Masahiko

    JOURNAL OF COMPARATIVE NEUROLOGY   525 巻 ( 7 ) 頁: 1558 - 1585   2017年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Comparative Neurology  

    The structure of the neural circuitry of the cerebellum, which functions in some types of motor learning and coordination, is generally conserved among vertebrates. However, some cerebellar features are species specific. It is not clear which genes are involved in forming these conserved and species-specific structures and functions. This study uses zebrafish transgenic larvae expressing fluorescent proteins in granule cells, Purkinje cells, or other cerebellar neurons and glial cells to isolate each type of cerebellar cells by fluorescence-activated cell sorting and to profile their gene expressions by RNA sequencing and in situ hybridization. We identify genes that are upregulated in granule cells or Purkinje cells, including many genes that are also expressed in mammalian cerebella. Comparison of the transcriptomes in granule cells and Purkinje cells in zebrafish larvae reveals that more developmental genes are expressed in granule cells, whereas more neuronal-function genes are expressed in Purkinje cells. We show that some genes that are upregulated in granule cells or Purkinje cells are also expressed in the cerebellum-like structures. Our data provide a platform for understanding the development and function of the cerebellar neural circuits in zebrafish and the evolution of cerebellar circuits in vertebrates. J. Comp. Neurol. 525:1558–1585, 2017. © 2016 Wiley Periodicals, Inc.

    DOI: 10.1002/cne.24114

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  20. Oncogenic role of rab escort protein 1 through EGFR and STAT3 pathway

    Yun Un-Jung, Sung Jee Young, Park Seog-Yun, Ye Sang-Kyu, Shim Jaegal, Lee Jae-Seon, Hibi Masahiko, Bae Young-Ki, Kim Yong-Nyun

    CELL DEATH & DISEASE   8 巻 ( 2 ) 頁: e2621   2017年2月

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    記述言語:日本語   出版者・発行元:Cell Death and Disease  

    Rab escort protein-1 (REP1) is linked to choroideremia (CHM), an X-linked degenerative disorder caused by mutations of the gene encoding REP1 (CHM). REP1 mutant zebrafish showed excessive cell death throughout the body, including the eyes, indicating that REP1 is critical for cell survival, a hallmark of cancer. In the present study, we found that REP1 is overexpressed in human tumor tissues from cervical, lung, and colorectal cancer patients, whereas it is expressed at relatively low levels in the normal tissue counterparts. REP1 expression was also elevated in A549 lung cancer cells and HT-29 colon cancer cells compared with BEAS-2B normal lung and CCD-18Co normal colon epithelial cells, respectively. Interestingly, short interfering RNA (siRNA)-mediated REP1 knockdown-induced growth inhibition of cancer cell lines via downregulation of EGFR and inactivation of STAT3, but had a negligible effect on normal cell lines. Moreover, overexpression of REP1 in BEAS-2B cells enhanced cell growth and anchorage-independent colony formation with little increase in EGFR level and STAT3 activation. Furthermore, REP1 knockdown effectively reduced tumor growth in a mouse xenograft model via EGFR downregulation and STAT3 inactivation in vivo. These data suggest that REP1 plays an oncogenic role, driving tumorigenicity via EGFR and STAT3 signaling, and is a potential therapeutic target to control cancers.

    DOI: 10.1038/cddis.2017.50

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  21. Osteocrin, a peptide secreted from the heart and other tissues, contributes to cranial osteogenesis and chondrogenesis in zebrafish

    Chiba Ayano, Watanabe-Takano Haruko, Terai Kenta, Fukui Hajime, Miyazaki Takahiro, Uemura Mami, Hashimoto Hisashi, Hibi Masahiko, Fukuhara Shigetomo, Mochizuki Naoki

    DEVELOPMENT   144 巻 ( 2 ) 頁: 334 - 344   2017年1月

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    記述言語:日本語   出版者・発行元:Development (Cambridge)  

    The heart is an endocrine organ, as cardiomyocytes (CMs) secrete natriuretic peptide (NP) hormones. Since the discovery of NPs, no other peptide hormones that affect remote organs have been identified from the heart. We identified osteocrin (Ostn) as an osteogenesis/chondrogenesis regulatory hormone secreted from CMs in zebrafish. ostn mutant larvae exhibit impaired membranous and chondral bone formation. The impaired bones were recovered by CM-specific overexpression of OSTN. We analyzed the parasphenoid (ps) as a representative of membranous bones. In the shortened ps of ostn morphants, nuclear Yap1/Wwtr1-dependent transcription was increased, suggesting that Ostn might induce the nuclear export of Yap1/Wwtr1 in osteoblasts. Although OSTN is proposed to bind to NPR3 (clearance receptor for NPs) to enhance the binding of NPs to NPR1 or NPR2, OSTN enhanced C-type NP (CNP)-dependent nuclear export of YAP1/WWTR1 of cultured mouse osteoblasts stimulated with saturable CNP. OSTN might therefore activate unidentified receptors that augment protein kinase G signaling mediated by a CNP-NPR2 signaling axis. These data demonstrate that Ostn secreted from the heart contributes to bone formation as an endocrine hormone.

    DOI: 10.1242/dev.143354

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  22. REP1 inhibits FOXO3-mediated apoptosis to promote cancer cell survival

    Song Kwon-Ho, Woo Seon Rang, Chung Joon-Yong, Lee Hyo-Jung, Oh Se Jin, Hong Soon-Oh, Shim Jaegal, Kim Yong Nyun, Rho Seung Bae, Hong Seung-Mo, Cho Hanbyoul, Hibi Masahiko, Bae Dong-Jun, Kim Sang-Yeob, Kim Min Gyu, Kim Tae Woo, Bae Young-Ki

    CELL DEATH & DISEASE   8 巻 ( 1 ) 頁: e2536   2017年1月

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    記述言語:日本語   出版者・発行元:Cell Death and Disease  

    Rab escort protein 1 (REP1) is a component of Rab geranyl-geranyl transferase 2 complex. Mutations in REP1 cause a disease called choroideremia (CHM), which is an X-linked eye disease. Although it is postulated that REP1 has functions in cell survival or death of various tissues in addition to the eye, how REP1 functions in normal and cancer cells remains to be elucidated. Here, we demonstrated that REP1 is required for the survival of intestinal cells in addition to eyes or a variety of cells in zebrafish, and also has important roles in tumorigenesis. Notably, REP1 is highly expressed in colon cancer tissues and cell lines, and silencing of REP1 sensitizes colon cancer cells to serum starvation- and 5-FU-induced apoptosis. In an effort to elucidate the molecular mechanisms underlying REP1-mediated cell survival under those stress conditions, we identified FOXO3 as a binding partner of REP1 using a yeast two-hybrid (Y2H) assay system, and we demonstrated that REP1 blocked the nuclear trans-localization of FOXO3 through physically interacting with FOXO3, thereby suppressing FOXO3-mediated apoptosis. Importantly, the inhibition of REP1 combined with 5-FU treatment could lead to significant retarded tumor growth in a xenograft tumor model of human cancer cells. Thus, our results suggest that REP1 could be a new therapeutic target in combination treatment for colon cancer patients.

    DOI: 10.1038/cddis.2016.462

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  23. Axis Formation and Its Evolution in Ray-Finned Fish

    Hibi Masahiko, Takeuchi Masaki, Hashimoto Hisashi, Shimizu Takashi

    REPRODUCTIVE AND DEVELOPMENTAL STRATEGIES: THE CONTINUITY OF LIFE     頁: 709 - +   2018年

  24. Granule cells control recovery from classical conditioned fear responses in the zebrafish cerebellum. 査読有り

    Matsuda, K., Yoshida, M., Kawakami, K., Hibi, M., Shimizu, T.

    Scientific Reports   7 巻 ( 1 ) 頁: 11865   2017年9月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/s41598-017-10794-0

  25. Granule cells control recovery from classical conditioned fear responses in the zebrafish cerebellum

    Matsuda Koji, Yoshida Masayuki, Kawakami Koichi, Hibi Masahiko, Shimizu Takashi

    SCIENTIFIC REPORTS   7 巻   2017年9月

  26. Medaka and zebrafish contactin1 mutants as a model for understanding neural circuits for motor coordination

    Takeuchi Miki, Inoue Chikako, Goshima Akiko, Nagao Yusuke, Shimizu Koichi, Miyamoto Hiroki, Shimizu Takashi, Hashimoto Hisashi, Yonemura Shigenobu, Kawahara Atsuo, Hirata Yutaka, Yoshida Masayuki, Hibi Masahiko

    GENES TO CELLS   22 巻 ( 8 ) 頁: 723 - 741   2017年8月

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  27. Medaka and zebrafish contactin1 mutants as a model for understanding neural circuits for motor coordination. 査読有り

    Takeuchi, M., Inoue, C., Goshima, A., Nagao, Y., Shimizu, K., Miyamoto, H., Shimizu, T., Hashimoto, H., Yonemura, S., Kawahara, A., Hirata, Y., Yoshida, M., Hibi, M.

    Genes to Cells   22 巻 ( 8 ) 頁: 723-741   2017年6月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/gtc.12509

  28. Evolutionary mechanisms that generate morphology and neural-circuit diversity of the cerebellum. 招待有り 査読有り

    Hibi, M., Matsuda, K., Takeuchi, M., Shimizu, T., Murakami, Y.

    Development, Growth & Differentiation   59 巻 ( 4 ) 頁: 228-243   2017年5月

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    担当区分:筆頭著者   記述言語:英語  

    DOI: 10.1111/dgd.12349

  29. Evolutionary mechanisms that generate morphology and neural-circuit diversity of the cerebellum

    Hibi Masahiko, Matsuda Koji, Takeuchi Miki, Shimizu Takashi, Murakami Yasunori

    DEVELOPMENT GROWTH & DIFFERENTIATION   59 巻 ( 4 ) 頁: 228 - 243   2017年5月

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  30. Type IV Collagen Controls the Axogenesis of Cerebellar Granule Cells by Regulating Basement Membrane Integrity in Zebrafish 査読有り

    Takeuchi, M., Yamaguchi, S., Yonemura, S., Kakiguchi, K., Sato, Y., Higashiyama, T., Shimizu, T., and Hibi M.

    PLOS Genetics   11 巻 ( 10 ) 頁: e1005587   2015年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1371/journal.pgen.1005587

  31. Establishment of Gal4 transgenic zebrafish lines for analysis of development of cerebellar neural circuitry 査読有り

    Takeuchi, M., Matsuda, K., Yamaguchi, S., Asakawa, K., Miyasaka, N. Lal, P., Yoshihara, Y., Koga, A., Kawakami, K., Shimizu, T., and Hibi, M.

    Developmental Biology   397 巻 ( 1 ) 頁: 1-17   2015年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.ydbio.2014.09.030.

  32. Sox5 functions as a fate switch in medic pigment cell development. 査読有り

    Nagao, Y., Suzuki, T., Shimizu, A., Kimura, T., Seki, R., Adachi, T., Inoue, C., Omae, Y., Kamei, Y., Hara, I., Taniguchi, Y., Naruse, K., Wakamatsu, Y., Kelsh, R. N., Hibi, M., and Hashimoto, H.

    PLOS Genetics   10 巻   頁: e1004246   2014年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1371/journal.pgen.1004246

  33. Development and evolution of cerebellar neural circuits 招待有り 査読有り

    Hashimoto, M. and Hibi, M.

    Development, Growth & Differentiation   54 巻 ( 3 ) 頁: 373-389   2012年4月

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    担当区分:筆頭著者   記述言語:英語  

    DOI: 10.1111/j

  34. Development of the cerebellum and cerebellar neural circuits. 招待有り 査読有り

    Hibi, M. and Shimizu, T.

    Developmental Neurobiology     2012年3月

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    担当区分:筆頭著者   記述言語:英語  

    DOI: 10.1002/dneu.20875

  35. Atypical PKC regulates primary dendrite specification of cerebellar Purkinje cells by localizing Golgi apparatus. 査読有り

    Tanabe, K., Kani, S., Shimizu, T., Bae, Y.-K., Abe, T., and Hibi, M.

    Journal of Neuroscience   30 巻   頁: 16983-16992   2010年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  36. Proneural gene-linked neurogenesis in zebrafish cerebellum. 査読有り

    Kani, S., Bae, Y.-K., Shimizu, T., Tanabe, K., Satou, C., Parsons, M.J. Scott, E., Higashijima, S.-I., and Hibi, M.

      343 巻   頁: 1-17   2010年7月

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  37. Zinc finger genes Fezf1 and Fezf2 control neuronal differentiation by repressing Hes5 expression in forebrain. 査読有り

    Shimizu, T., Nakazawa, M., Kani, S., Bae, Y.-K., Shimizu, T., Kageyama, R., Hibi, M.

    Development   137 巻   頁: 1875-1885   2010年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  38. Syntabulin, a motor protein linker, controls dorsal determination. 査読有り

    Nojima, H., Rothhämel, S., Shimizu, T., Kim, C.H., Yonemura, S., Marlow, F.L., Hibi, M.

    Development   137 巻   頁: 923-933   2010年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  39. Formation and patterning of the forebrain and olfactory system by zinc finger genes Fezf1 and Fezf2 招待有り 査読有り

    Shimizu, T. and Hibi, M.

    Development, Growth & Differentiation   51 巻 ( 3 ) 頁: 221-231   2009年4月

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    担当区分:筆頭著者   記述言語:英語  

  40. Anatomy of zebrafish cerebellum and screen for mutations affecting its development. 査読有り

    Bae, Y.-K., Kani, S., Shimizu, T., Tanabe, K., Nojima, H., Kimura, Y., Higashijima, S., and Hibi, M.

    Developmental Biology   330 巻   頁: 406-426   2009年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  41. Cdx-Hox code controls competence for responding to Fgfs and retinoic acid in zebrafish neural tissue. 査読有り

    Shimizu, T., Bae, Y.-K., and Hibi, M.

    Development   133 巻   頁: 4709-4719   2006年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  42. Zinc-finger gene Fez in the olfactory neurons regulates development of the olfactory bulb non-cell-autonomously. 査読有り

    Hirata, T., Nakazawa, M., Yoshihara, S., Miyachi, H., Kitamura, K., Yoshihara, Y., and Hibi, M.

    Development   133 巻   頁: 1433-1443   2006年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  43. Sizzled controls dorso-ventral polarity by repressing cleavage of the Chordin protein. 査読有り

    Muraoka, O., Shimizu, T., Yabe, T., Nojima, H., Bae, Y-K., Hashimoto, H., and Hibi, M.

    Nature Cell Biology   8 巻   頁: 329-340   2006年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  44. Zinc-finger genes Fez and Fez-like function in the establishment of diencephalon subdivisions. 査読有り

    Hirata, T., Nakazawa, M., Muraoka, O., Nakayama, R., Suda, Y., and Hibi, M.

    Development   133 巻   頁: 3993-4004   2006年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

▼全件表示

書籍等出版物 2

  1. From Cerebellar Genes to Behaviors in Zebrafish

    Hibi M., Shimizu T.

    Neuromethods  2022年 

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    記述言語:日本語

    The cerebellum is involved in some forms of motor coordination and learning, and also in non-motor cognitive and emotional functions. These functions of the cerebellum rely on the structure of the neural circuit which is generally conserved among vertebrates. As the zebrafish became a versatile animal model to study the development and function of the vertebrate brain, its cerebellum was studied over the last decade. Although the zebrafish cerebellum has a small and simple structure, it has layer and neural circuit structures as well as motor and non-motor functions similar to the mammalian cerebellum, and the same genetic program. Therefore, the zebrafish cerebellum is a good model for understanding the development and function of the cerebellum of mammals, including humans. In this review, we outline the structure and development of the zebrafish cerebellum, and explain the molecular and transgenic tools that are used to study it. Finally, we discuss how studies on the zebrafish cerebellar circuits contribute to our understanding the vertebrate cerebellum and human diseases caused by cerebellar defects.

    DOI: 10.1007/978-1-0716-2026-7_2

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  2. ゼブラフィッシュ実験ガイド

    日比 正彦、清水 貴史、橋本 寿史、井原 邦夫( 担当: 分担執筆 ,  範囲: 第17章 実験に必要な手続き)

    朝倉書店  2020年11月 

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    総ページ数:135   担当ページ:125-132   記述言語:日本語 著書種別:教科書・概説・概論

科研費 9

  1. 小脳神経回路形成に関わるニューロン分化の遺伝プログラムの解明

    研究課題/研究課題番号:18H02448  2018年4月 - 2021年3月

    科学研究費補助金 

    日比 正彦

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    担当区分:研究代表者 

    配分額:17420000円 ( 直接経費:13400000円 、 間接経費:4020000円 )

    (1)下オリーブ核ニューロンの分化機構の解析
    私達はこれまで、プロニューラル因子Ptf1aとホメオボックス転写因子Gsx2の変異体で、下オリーブ核ニューロンが減少・消失することを見出した。ptf1a変異体ではgsx2の発現が変化せずgsx2変異体ではptf1aの発現が変化しないこと、ptf1a変異体ではアポトーシスを誘導するがgsx2変異体では誘導しないことから、Ptf1aとGsx2は独立した機能をもって下オリーブ核ニューロン分化を制御していると考えられた。また、Fgf3/8aとレチノイン酸のシグナルがそれぞれ負と正にgsx2の発現を制御しており、mafbaとhox遺伝子がそれぞれFgfとレチノイン酸シグナルの下流でgsx2の発現を制御することで、下オリーブ核ニューロンの分化に関わっていることを見出した。これらの結果は、Gsx2が前後軸の位置情報シグナルを受け、Ptf1a発現細胞から下オリーブ核ニューロンへの運命決定に関与していることを示している(論文投稿リバイス中)。
    (2)プルキンエ細胞の分化機構の解析
    私達はこれまで、プルキンエ細胞に発現する転写因子Foxp1bとFoxp4のダブル変異体でプルキンエ細胞が大幅に減少し、同じくプルキンエ細胞に発現する転写共抑制因子Skor1bとSkor2のダブル変異体ではプルキンエ細胞が消失し代わりに顆粒細胞が増加することを見出した。これらの結果から、Foxp1b/4はプルキンエ細胞分化遺伝子を正に制御し、Skor1b/2は顆粒細胞分化遺伝子の発現を抑制している可能性が示唆された。Foxpタンパク質はDNAに直接結合するが、Skorタンパク質は他の転写因子を介してDNAに結合すると考えられている。私達は、Skor1b/2に結合する転写因子の候補として、プルキンエ細胞に発現するLhxファミリータンパク質Lhx1a/1b/5を見出した。
    下オリーブ核ニューロンの分化機構に関しては詳細なメカニズムが分かり、論文の形にし投稿しリバイス中である。下オリーブ核ニューロンの分化機構に重要な役割を持つgsx2の発現機構を検討するため、エンハンサー解析を始めており、研究は順調に進展している。一方、プルキンエ細胞の分化機構の解析に関しては、転写共抑制因子Skor1b/2のパートナー候補が見つかり、メカニズムに迫りつつある。Skor1b/2および転写因子Foxp1b/4の標的遺伝子を、クロマチン免疫沈降で解析するための準備も進んでいる。計画全体として、おおむね順調に進展していると判断できる。
    (1)gsx2の発現制御機構の解析:マウスGsx2遺伝子の比較解析から、gsx2の下オリーブ核ニューロン前駆細胞での発現に関わるエンハンサー領域が推定出来ている。エンハンサーの変異体を作製し、トランスジェニックフィッシュを作製することで、発現に必要なDNA領域を決定し、そこに結合する転写因子を同定する。
    (2)foxp1b/4、skor1b/2の異所的発現による機能解析:これらの遺伝子を単独で、またはfoxpとskor遺伝子、skorとlhx遺伝子を組み合わせて、顆粒細胞系譜に発現し、顆粒細胞の分化を抑制しプルキンエ細胞への運命転化を起こせるかを検討する。
    (3)Skor1b/2の機能におけるLhxタンパク質の役割の解析:SkorとLhxの相互作用に関与するSkorとLhxタンパク質のドメインを同定する。同定したドメインを欠失した変異タンパク質の顆粒細胞の分化抑制機能を検討する。さらにlhx1a/1b/5のトリプル変異体を作製し表現型を解析するとともに、Lhx1a/1b/5非存在下でSkor1b/2の機能解析を行う。
    (4)Foxp1b/4、Skor1b/2、Gsx2の標的遺伝子の探索:ビオチンリガーゼ認識ペブチドを融合したFoxp1b/4、Skor1b/2をプルキンエ細胞に、同Gsx2を下オリーブ核ニューロン前駆細胞に発現させたトランスジェニックフィッシュの脳から、転写制御因子に結合したDNAを、ストレプトアビジンを用いて回収し配列を決定することで、これら転写制御因子の標的遺伝子を探索する。さらに、これら標的遺伝子の機能解析を行う。

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▼全件表示

 

担当経験のある科目 (本学) 14

  1. 遺伝学I

    2015

  2. 分子生物学演習I

    2015

  3. 基礎遺伝学III

    2015

  4. 生物学入門

    2015

  5. 分子生物学演習I

    2014

  6. 遺伝学I

    2014

  7. 生物学入門

    2014

  8. 基礎セミナーB

    2014

  9. 基礎遺伝学III

    2013

  10. 分子生物学演習Ⅰ

    2013

  11. 遺伝学I

    2013

  12. 基礎遺伝学III

    2012

  13. 分子生物学演習Ⅰ

    2012

  14. 基礎セミナーA

    2011

▼全件表示