Updated on 2022/04/12

写真a

 
OHSAWA Shizue
 
Organization
Graduate School of Science Professor
Graduate School
Graduate School of Science
Undergraduate School
School of Science Department of Biological Science
Title
Professor

Degree 2

  1. 博士(薬学) ( 2008.3   東京大学 ) 

  2. 修士(医科学) ( 2005.3   大阪大学 ) 

Research Areas 1

  1. Life Science / Developmental biology

Committee Memberships 2

  1. 日本発生生物学会   副幹事長  

    2021.6   

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    Committee type:Academic society

  2. 日本細胞生物学会   男女共同参画・若手育成委員  

    2020.6   

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    Committee type:Academic society

 

Papers 14

  1. Epithelial cell-turnover ensures robust coordination of tissue growth in Drosophila ribosomal protein mutants Reviewed International journal

    Nanami Akai, Shizue Ohsawa, Yukari Sando, Tatsushi Igaki

    PLOS Genetics   Vol. 17 ( 1 ) page: e1009300 - e1009300   2021.1

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Public Library of Science (PLoS)  

    Highly reproducible tissue development is achieved by robust, time-dependent coordination of cell proliferation and cell death. To study the mechanisms underlying robust tissue growth, we analyzed the developmental process of wing imaginal discs in <italic>Drosophila Minute</italic> mutants, a series of heterozygous mutants for a ribosomal protein gene. <italic>Minute</italic> animals show significant developmental delay during the larval period but develop into essentially normal flies, suggesting there exists a mechanism ensuring robust tissue growth during abnormally prolonged developmental time. Surprisingly, we found that both cell death and compensatory cell proliferation were dramatically increased in developing wing pouches of <italic>Minute</italic> animals. Blocking the cell-turnover by inhibiting cell death resulted in morphological defects, indicating the essential role of cell-turnover in <italic>Minute</italic> wing morphogenesis. Our analyses showed that <italic>Minute</italic> wing discs elevate Wg expression and JNK-mediated Dilp8 expression that causes developmental delay, both of which are necessary for the induction of cell-turnover. Furthermore, forced increase in Wg expression together with developmental delay caused by ecdysone depletion induced cell-turnover in the wing pouches of non-<italic>Minute</italic> animals. Our findings suggest a novel paradigm for robust coordination of tissue growth by cell-turnover, which is induced when developmental time axis is distorted.

    DOI: 10.1371/journal.pgen.1009300

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  2. Yorkie drives supercompetition by non-autonomous induction of autophagy via bantam microRNA in Drosophila. Reviewed

    Nagata R, Akai N, Kondo S, Saito K, Ohsawa S, Igaki T

    Current biology : CB     2022.1

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

    DOI: 10.1016/j.cub.2022.01.016

    PubMed

  3. JNK and Yorkie drive tumor malignancy by inducing L-amino acid transporter 1 in Drosophila Reviewed

    Cong Bojie, Nakamura Mai, Sando Yukari, Kondo Takefumi, Ohsawa Shizue, Igaki Tatsushi

      Vol. 17 ( 11 ) page: e1009893   2021.11

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

    DOI: 10.1371/journal.pgen.1009893

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  4. Yorkie ensures robust tissue growth in Drosophila ribosomal protein mutants Reviewed

    Wada Yayoi, Ohsawa Shizue, Igaki Tatsushi

    DEVELOPMENT   Vol. 148 ( 14 )   2021.7

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    Language:English   Publisher:Development (Cambridge)  

    Heterozygosity of ribosomal protein genes causes a variety of developmental abnormalities in humans, which are collectively known as ribosomopathies, yet the underlying mechanisms remain elusive. Here, we analyzed Drosophila Minute (M)/+ mutants, a group of mutants heterozygous for ribosomal protein genes that exhibit a characteristic thin-bristle phenotype. We found that, although M/+ flies develop essentially normal wings, simultaneous deletion of one copy of the Hippo pathway effector yki resulted in severe wing growth defects. These defects were caused by JNK-mediated cell death in the wing pouch via Eiger/TNF signaling. The JNK activation in M/+, yki/+ wing discs required the caspase Dronc, which is normally blocked by DIAP1. Notably, heterozygosity of yki reduced DIAP1 expression in the wing pouch, leading to elevation of Dronc activity. Dronc and JNK formed a positive-feedback loop that amplifies Dronc activation, leading to apoptosis. Our observations suggest a mechanism of robust tissue growth whereby tissues with reduced ribosomal protein prevent ectopic apoptosis via Yki activity.

    DOI: 10.1242/dev.198705

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  5. JNK-mediated Slit-Robo signaling facilitates epithelial wound repair by extruding dying cells. Reviewed International coauthorship International journal

    Iida C, Ohsawa S, Taniguchi K, Yamamoto M, Morata G, Igaki T

    Scientific reports   Vol. 9 ( 1 ) page: 19549   2019.12

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

    DOI: 10.1038/s41598-019-56137-z

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  6. Elimination of oncogenic cells that regulate epithelial homeostasis in Drosophila. Invited Reviewed International journal

    Shizue Ohsawa

    Development, Growth & Differentiation   Vol. 61 ( 5 ) page: 337 - 342   2019.6

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

    DOI: 10.1111/dgd.12604.

  7. Competition for Space Is Controlled by Apoptosis-Induced Change of Local Epithelial Topology. Reviewed International journal

    Alice Tsuboi, Shizue Ohsawa, Daiki Umetsu, Yukari Sando, Erina Kuranaga, Tatsushi Igaki, Koichi Fujimoto

    Current biology : CB   Vol. 28 ( 13 ) page: 2115 - 2128.e5   2018.7

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

    During the initial stage of tumor progression, oncogenic cells spread despite spatial confinement imposed by surrounding normal tissue. This spread of oncogenic cells (winners) is thought to be governed by selective killing of surrounding normal cells (losers) through a phenomenon called "cell competition" (i.e., supercompetition). Although the mechanisms underlying loser elimination are increasingly apparent, it is not clear how winner cells selectively occupy the space made available following loser apoptosis. Here, we combined live imaging analyses of two different oncogenic clones (Yki/YAP activation and Ras activation) in the Drosophila epithelium with computer simulation of tissue mechanics to elucidate such a mechanism. Contrary to the previous expectation that cell volume loss after apoptosis of loser cells was simply compensated for by the faster proliferation of winner cells, we found that the lost volume was compensated for by rapid cell expansion of winners. Mechanistically, the rapid winner-dominated cell expansion was driven by apoptosis-induced epithelial junction remodeling, which causes re-connection of local cellular connectivity (cell topology) in a manner that selectively increases winner apical surface area. In silico experiments further confirmed that repetition of loser elimination accelerates tissue-scale winner expansion through topological changes over time. Our proposed mechanism for linking loser death and winner expansion provides a new perspective on how tissue homeostasis disruption can initiate from an oncogenic mutation.

    DOI: 10.1016/j.cub.2018.05.029

    PubMed

  8. Serpin Facilitates Tumor-Suppressive Cell Competition by Blocking Toll-Mediated Yki Activation in Drosophila Reviewed International coauthorship International journal

    Mitsuko Katsukawa, Shizue Ohsawa, Lina Zhang, Yan Yan, Tatsushi Igaki

    Current Biology   Vol. 28 ( 11 ) page: 1756 - 1767.e6   2018.6

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Cell Press  

    Normal epithelial tissue exerts an intrinsic tumor-suppressive effect against oncogenically transformed cells. In Drosophila imaginal epithelium, clones of oncogenic polarity-deficient cells mutant for scribble (scrib) or discs large (dlg) are eliminated by cell competition when surrounded by wild-type cells. Here, through a genetic screen in Drosophila, we identify Serpin5 (Spn5), a secreted negative regulator of Toll signaling, as a crucial factor for epithelial cells to eliminate scrib mutant clones from epithelium. Downregulation of Spn5 in wild-type cells leads to elevation of Toll signaling in neighboring scrib cells. Strikingly, forced activation of Toll signaling or Toll-related receptor (TRR) signaling in scrib clones transforms scrib cells from losers to supercompetitors, resulting in tumorous overgrowth of mutant clones. Mechanistically, Toll activation in scrib clones leads to c-Jun N-terminal kinase (JNK) activation and F-actin accumulation, which cause strong activation of the Hippo pathway effector Yorkie that blocks cell death and promotes cell proliferation. Our data suggest that Spn5 secreted from normal epithelial cells acts as a component of the extracellular surveillance system that facilitates elimination of pre-malignant cells from epithelium. Normal epithelial tissue exerts antitumor effect against oncogenically transformed cells. Katsukawa et al. show in Drosophila epithelium that Spn5, a secreted negative regulator of Toll signaling, acts as a surveillance factor that facilitates cell-competition-mediated elimination of pre-malignant cells by preventing Yorkie activation.

    DOI: 10.1016/j.cub.2018.04.022

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  9. JNK and Yorkie drive tumor progression by generating polyploid giant cells in Drosophila Reviewed International journal

    Bojie Cong, Shizue Ohsawa, Tatsushi Igaki

    Oncogene   Vol. 37 ( 23 ) page: 3088 - 3097   2018.6

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Nature Publishing Group  

    Epithelial cancer tissues often possess polyploid giant cells, which are thought to be highly oncogenic. However, the mechanisms by which polyploid giant cells are generated in tumor tissues and how such cells contribute to tumor progression remain elusive. We previously noticed in Drosophila imaginal epithelium that cells mutant for the endocytic gene rab5 exhibit enlarged nuclei. Here we find that mutations in endocytic 'neoplastic tumor-suppressor' genes, such as rab5, vps25, erupted, or avalanche result in generation of polyploid giant cells. Genetic analyses on rab5-defective cells reveal that cooperative activation of JNK and Yorkie generates polyploid giant cells via endoreplication. Mechanistically, Yorkie-mediated upregulation of Diap1 cooperates with JNK to downregulate the G2/M cyclin CycB, thereby inducing endoreplication. Interestingly, malignant tumors induced by Ras activation and cell polarity defect also consist of polyploid giant cells, which are generated by JNK and Yorkie-mediated downregulation of CycB. Strikingly, elimination of polyploid giant cells from such malignant tumors by blocking endoreplication strongly suppressed tumor growth and metastatic behavior. Our observations suggest that JNK and Yorkie, two oncogenic proteins activated in many types of human cancers, cooperatively drive tumor progression by generating oncogenic polyploid giant cells.

    DOI: 10.1038/s41388-018-0201-8

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  10. Wingless signaling regulates winner/loser status in Minute cell competition Reviewed International journal

    Nanami Akai, Tatsushi Igaki, Shizue Ohsawa

    Genes to Cells   Vol. 23 ( 3 ) page: 234 - 240   2018.3

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Blackwell Publishing Ltd  

    Cells heterozygously mutant for a ribosomal protein gene, called Minute/+ mutants, are eliminated from epithelium by cell competition when surrounded by wild-type cells. Whereas several factors that regulate Minute cell competition have been identified, the mechanisms how winner/loser status is determined and thereby triggers cell competition are still elusive. To address this, we established two assay systems for Minute cell competition, namely (i) the CORE (competitive elimination of RpS3-RNAi-expressing cells) system in which RpS3-RNAi-expressing wing pouch cells are eliminated from wild-type wing disc and (ii) the SURE (supercompetition of RpS3-expressing clones in RpS3/+ tissue) system in which RpS3-over-expressing clones generated in RpS3/+ wing disc outcompete surrounding RpS3/+ cells. An ectopic over-expression screen using the CORE system identified Wg signaling as a critical regulator of Minute cell competition. Activation of Wg signaling in loser cells suppressed their elimination, whereas down-regulation of Wg signaling in loser cells enhanced their elimination. Furthermore, using the SURE system, we found that down-regulation of Wg signaling in winner cells suppressed elimination of neighboring losers. Our observations suggest that cellular Wg signaling activity is crucial for determining winner/loser status and thereby triggering Minute cell competition.

    DOI: 10.1111/gtc.12568

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  11. Cell Extrusion: A Stress-Responsive Force for Good or Evil in Epithelial Homeostasis Reviewed International coauthorship International journal

    Shizue Ohsawa, John Vaughen, Tatsushi Igaki

    Developmental Cell   Vol. 44 ( 3 ) page: 284 - 296   2018.2

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Cell Press  

    Epithelial tissues robustly respond to internal and external stressors via dynamic cellular rearrangements. Cell extrusion acts as a key regulator of epithelial homeostasis by removing apoptotic cells, orchestrating morphogenesis, and mediating competitive cellular battles during tumorigenesis. Here, we delineate the diverse functions of cell extrusion during development and disease. We emphasize the expanding role for apoptotic cell extrusion in exerting morphogenetic forces, as well as the strong intersection of cell extrusion with cell competition, a homeostatic mechanism that eliminates aberrant or unfit cells. While cell competition and extrusion can exert potent, tumor-suppressive effects, dysregulation of either critical homeostatic program can fuel cancer progression. Epithelial tissues robustly respond to internal and external stressors via dynamic cellular rearrangements. Cell extrusion acts as a key regulator of epithelial homeostasis by removing apoptotic cells, orchestrating morphogenesis, and mediating competitive cellular battles during tumorigenesis. Ohsawa et al. delineate the diverse functions of cell extrusion during development and disease.

    DOI: 10.1016/j.devcel.2018.01.009

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  12. 細胞競合の勝敗を規定する組織環境条件の遺伝学および数理学的解析

    片山 宰, 西川 星也, 大澤 志津江, 高松 敦子, 井垣 達吏

    生命科学系学会合同年次大会   Vol. 2017年度   page: [3PT19 - 0392)]   2017.12

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    Language:Japanese   Publisher:生命科学系学会合同年次大会運営事務局  

  13. The ligand Sas and its receptor PTP1OD drive tumour-suppressive cell competition Reviewed International journal

    Masatoshi Yamamoto, Shizue Ohsawa, Kei Kunimasa, Tatsushi Igaki

    NATURE   Vol. 542 ( 7640 ) page: 246 - 250   2017.2

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:NATURE PUBLISHING GROUP  

    Normal epithelial cells often exert anti-tumour effects against nearby oncogenic cells. In the Drosophila imaginal epithelium, clones of oncogenic cells with loss-of-function mutations in the apico-basal polarity genes scribble or discs large are actively eliminated by cell competition when surrounded by wild-type cells'. Although c-Jun N-terminal kinase (JNK) signalling plays a crucial role in this cell elimination(1-5), the initial event, which occurs at the interface between normal cells and polarity-deficient cells, has not previously been identified. Here, through a genetic screen in Drosophila, we identify the ligand Sas and the receptor-type tyrosine phosphatase PTP10D as the cell-surface ligand-receptor system that drives tumour-suppressive cell competition. At the interface between the wild-type 'winner' and the polarity-deficient 'loser' clones, winner cells relocalize Sas to the lateral cell surface, whereas loser cells relocalize PTP10D there. This leads to the trans activation of Sas-PTP10D signalling in loser cells, which restrains EGFR signalling and thereby enables elevated JNK signalling in loser cells, triggering cell elimination. In the absence of Sas-PTP10D, elevated EGFR signalling in loser cells switches the role of JNK from pro-apoptotic to pro-proliferative by inactivating the Hippo pathway, thereby driving the overgrowth of polarity-deficient cells. These findings uncover the mechanism by which normal epithelial cells recognize oncogenic polarity-deficient neighbours to drive cell competition.

    DOI: 10.1038/nature21033

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  14. Mechanical occupation of the lost territory by winners during cell competition

    Tsuboi Alice, Ohsawa Shizue, Igaki Tatsushi, Fujimoto Koichi

    Meeting Abstracts of the Physical Society of Japan   Vol. 72 ( 0 ) page: 3125 - 3125   2017

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    Language:Japanese   Publisher:The Physical Society of Japan  

    DOI: 10.11316/jpsgaiyo.72.1.0_3125

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Presentations 15

  1. 細胞間コミュニケーションによる生体制御 Invited

    大澤 志津江

    生物科学セミナー  2021.12.15  入江直樹博士(東京大学大学院理学研究科)

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    Event date: 2021.12

    Language:Japanese   Presentation type:Public lecture, seminar, tutorial, course, or other speech  

    Venue:オンライン   Country:Japan  

  2. ショウジョウバエが明かすがんのバイオロジー Invited International coauthorship

    大澤 志津江

    第80回日本癌学会学術総会  2021.10.1 

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    Event date: 2021.10

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Venue:パシフィコ横浜  

  3. Yki/YAP ensures robust tissue morphogenesis by suppressing JNK-mediated cell death in Drosophila Invited

    2021.6.30 

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    Event date: 2021.6 - 2021.7

    Language:English   Presentation type:Oral presentation (invited, special)  

  4. Epithelial cell-turnover ensures robust coordination of tissue growth in Drosophila Invited

    2021.3.28 

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    Event date: 2021.3

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

  5. 細胞間コミュニケーションを介した発生ロバストネス制御 Invited

    大澤 志津江

    第70回日本細胞生物学会・第51回日本発生生物学会 合同大会  2018.6.7 

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    Language:Japanese   Presentation type:Public lecture, seminar, tutorial, course, or other speech  

  6. 細胞ターンオーバーを介した発生ロバストネスの遺伝的基盤 Invited

    大澤 志津江, 赤井 菜々美, 井垣 達吏

    ConBio2017  2017.12.7 

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    Language:Japanese   Presentation type:Oral presentation (invited, special)  

  7. 細胞ターンオーバーを介した発生ロバストネスの遺伝的基盤 Invited

    大澤 志津江

    第19回日本蛋白質科学会年会 第71回日本細胞生物学会大会 合同年次大会  2019.6.24 

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  8. Epithelial cell-turnover ensures robust coordination of tissue growth in Drosophila Invited International conference

    Shizue Ohsawa

    Key Forum 2018 “Stem Cell Traits and Developmental Systems”  2018.1.11 

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  9. 3D morphogenesis of Drosophila adult appendages from the Folded Epithelial Sheets Invited International conference

    Shizue Ohsawa

    Japan-UCI Meeting on 3D Morphogenesis  2017.7.10 

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  10. 折り畳まれた上皮組織から3D形態へと変形を開始するメカニズム Invited

    大澤 志津江

    第1回日本メカノバイオロジー研究会  2019.9.3 

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    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Venue:ベネッセアートサイト直島(香川)  

  11. 3D morphogenesis of adult appendages from the Folded Epithelial Sheets in Drosophila Invited International conference

    Shizue Ohsawa

    The 2nd NIBB-Princeton Joint Symposium ”Imaging and Quantitative Biology”  2019.10.28 

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  12. Epithelial cell-turnover ensures morphogenetic robustness in Drosophila Invited International conference

    Shizue Ohsawa

    Joint Meeting of the German and Japanese Societies of Developmental Biologists: GFE2017  2017.3.17 

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  13. 上皮の恒常性維持を司る細胞競合の分子基盤 Invited

    大澤 志津江

    第29回高遠・分子生物学シンポジウム  2017.8.24 

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  14. Elimination of oncogenic cells through tumor-suppressive cell competition in Drosophila Invited International conference

    Shizue Ohsawa

    2019.9.27 

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  15. Epithelial turn-over through cell competition ensures robust coordination of tissue growth in Drosophila Invited

    2020.12.2 

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    Language:English   Presentation type:Oral presentation (invited, special)  

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Research Project for Joint Research, Competitive Funding, etc. 12

  1. がん超早期・早期病変に対する細胞生物学的治療コンセプトの創出

    2020.12 - 2025.7

    ムーンショット 

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    Grant amount:\78000000 ( Direct Cost: \60000000 、 Indirect Cost:\18000000 )

  2. 細胞集団挙動を介した発生時間軸制御の遺伝的基盤

    2021.8 - 2023.3

    ライフサイエンス研究継続助成 

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    Authorship:Principal investigator 

    Grant amount:\3000000 ( Direct Cost: \3000000 )

  3. 競合的がん制御とその遺伝的基盤の解明

    2021.1 - 2022.12

    公益財団法人 MSD生命科学財団  公益財団法人 MSD生命科学財団「がん領域 スタートアップ」 

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\10000000 ( Direct Cost: \10000000 )

  4. 細胞ターンオーバーを介した発生時間軸補正とその分子機構の解明

    2020.11 - 2022.3

    公益財団法人 山田科学振興財団  公益財団法人 山田科学振興財団「研究援助」 

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\2000000 ( Direct Cost: \2000000 )

  5. がん微小環境を規定する細胞競合現象の遺伝的基盤

    2020 - 2023.3

    公益財団法人 第一三共生命科学研究振興財団  公益財団法人 第一三共生命科学研究振興財団 「PIセットアップ研究助成」 

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\3000000 ( Direct Cost: \3000000 )

  6. 競合が制御するがん微小環境とその分子基盤の解明

    2020 - 2022.9

    公益財団法人 アステラス病態代謝研究会  公益財団法人 アステラス病態代謝研究会「研究助成」 

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\2000000 ( Direct Cost: \2000000 )

  7. 細胞競合が規定するがん微小環境の遺伝的基盤

    2020 - 2022.3

    公益財団法人 大幸財団 「自然科学系学術研究助成」 

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    Authorship:Principal investigator  Grant type:Competitive

  8. 競合が規定するがん微小環境の分子基盤の解明 International coauthorship

    2020 - 2021.12

    公益財団法人 持田記念医学薬学振興財団  公益財団法人 持田記念医学薬学振興財団「研究助成金」 

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    Authorship:Principal investigator  Grant type:Competitive

  9. 細胞間コミュニケーションを介した発生時間軸制御

    2019 - 2022.3

    公益財団法人 東レ科学振興会  公益財団法人 東レ科学振興会「科学技術研究助成」 

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\10000000

  10. 細胞ターンオーバーを介した発生時間軸制御の遺伝的基盤

    2019 - 2021.3

    公益財団法人 稲盛財団  公益財団法人 稲盛財団「研究助成」 

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\2000000

  11. 細胞集団挙動による発生時間軸制御とその分子基盤の解明

    2019 - 2020.9

    公益財団法人 三菱財団 「自然科学研究助成」 

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\7000000

  12. 細胞間コミュニケーションを介した組織の時間軸制御機構の解明

    2018 - 2019.3

    公益財団法人 千里ライフサイエンス「岸本基金研究助成」 

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\2000000

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KAKENHI (Grants-in-Aid for Scientific Research) 10

  1. 昆虫外骨格形態を建築するECMリモデリングとその分子機構の解明

    Grant number:20H05945  2020.11 - 2025.3

    科学研究費助成事業  学術変革領域研究(A)

    大澤 志津江, 田尻 怜子

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\130780000 ( Direct Cost: \100600000 、 Indirect Cost:\30180000 )

    外骨格生物の多くは、脱皮前の外皮を折り畳んだ状態で作り、それを脱皮後に展開させることで形態形成を行う。しかしながら、「折り畳んだ状態で最終形態を作る仕組み」や、「折り畳まれた形態を展開する仕組み」はほとんど分かっていないのが現状である。本研究グループは、ショウジョウバエをモデル生物として導入し、折り畳み形成と展開の分子機構を、主にミクロレベルに焦点を当てた解析により明らかにする。得られた結果を、マクロレベルの解析を主に行う新美班の研究成果と統合させ、数理モデルとも組み合わせることで「折り畳みを介した形態形成」の基本法則を明らかにすることを最終目標とする。

  2. 3D morphogenesis of adult appendages from the folded epithelial sheets in Drosophila

    Grant number:15H05862  2015.6 - 2020.3

    Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Ohsawa Shizue

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\95290000 ( Direct Cost: \73300000 、 Indirect Cost:\21990000 )

    Adult external appendages of insects are generated from “folded” epithelial sheets called as imaginal discs. In this study, we found that down-regulation of type IV Collagen, a main component of the basal membrane on epithelial sheets, triggers deformation of the wing imaginal disc to the wing structure during development. Histochemical analyses revealed that downregulation of type IV Collagen alters the pattern of myosin II activation and Integrin after initiating the deformation of the wing disc. Our data suggest that remodeling of extracellular matrix could triggers autonomous deformation of the folded structure by regulating epithelial dynamics.

  3. 競合を介したがん微小環境制御とその遺伝的基盤の解明

    Grant number:21K19257  2021.7 - 2023.3

    日本学術振興会  科学研究費助成事業  挑戦的研究(萌芽)

    大澤 志津江

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\6500000 ( Direct Cost: \5000000 、 Indirect Cost:\1500000 )

    がんの発生やその進展において、細胞間相互作用により構築されるがん微小環境が重要な役割を果たすことが近年分かってきた。そして、このようながん制御の“場”の性質を規定する因子として、細胞同士の敵者生存競争「細胞競合」が注目されつつあるが、その分子実体はいまだ不明な点が多い。本研究では、ショウジョウバエ上皮をモデルとした生体レベルでの解析を展開し、細胞競合が「がん微小環境」の性質を規定・制御する遺伝的基盤の理解を目指す。

  4. 形態形成の原理の解明と工学への展開

    Grant number:20H05941  2020.11 - 2025.3

    科学研究費助成事業  学術変革領域研究(A)

    井上 康博, 船山 典子, 近藤 滋, 新美 輝幸, 大澤 志津江, 小沼 健, 秋山 正和, 山崎 慎太郎, 後藤 寛貴, 田尻 怜子

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    細胞は、素材によって工法を選び、組み立てることで「体」を建築する。本領域では、この素材の加工という新しいパラダイムを提示することで、後期発生以降の形態形成の原理に挑む。このパラダイムは「工業」そのものであるため、工業デザイン技術の生物への応用と、生物で得られた知見の産業応用が期待できる。この目的のために、総括班は、様々な分野の実験系と理論系の融合推進、異分野からの若手研究者の参入支援など、領域推進の司令塔としての機能を担う。

  5. 遺伝的細胞ダイバーシティーが駆動する”細胞非自律的”がん制御の遺伝的基盤

    Grant number:20H05032  2020.4 - 2022.3

    新学術領域研究(研究領域提案型)

    大澤 志津江

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\6240000 ( Direct Cost: \4800000 、 Indirect Cost:\1440000 )

    がんの発生やその進展は、異なる遺伝的背景を持つ細胞同士の競合現象「細胞競合」により、正にも負にも制御されることが近年分かってきたが、その分子実体はいまだ不明である。本研究ではショウジョウバエをモデルとし、細胞競合を介したがん促進現象(1)がん細胞が周辺細胞を駆逐しながらその領地を拡大していく“スーパーコンペティション”および(2)敗者から勝者へのスイッチングの分子機構を、遺伝学的手法やRNAseqを初めとした多角的アプローチにより解析する。さらに、両現象をつなぐ分子基盤を明らかにすることで、遺伝的細胞ダイバーシティーが駆動する細胞間相互作用の動作原理とそのがん制御機構の理解を目指す。

  6. 細胞ターンオーバーを介した表現型制約とその分子基盤の解明

    Grant number:20H04866  2020.4 - 2021.3

    科学研究費助成事業  新学術領域研究(研究領域提案型)

    大澤 志津江

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\10270000 ( Direct Cost: \7900000 、 Indirect Cost:\2370000 )

    我々は最近、幼虫期のショウジョウバエが種々の内的・外的撹乱により発生遅延を起こした際に、その遅延を補正する細胞集団挙動「細胞ターンオーバー」が翅原基で誘発されることを見いだした。興味深いことに、この細胞ターンオーバーを遺伝学的に抑制すると、種々の表現型が成虫翅に出現する。このことは、細胞ターンオーバー機構が表現型を制約する役割を担う可能性を示唆している。本研究では、表現型制約を行うこの未知の細胞集団挙動の分子基盤とその役割を明らかにする。それにより、「個体の成長遅延に呼応した細胞集団挙動の局所的変化」という、表現型制約を担う新たな発生ロバストネス原理の解明を目指す。
    多細胞生物の個体発生は、時間軸に沿った精密かつ計画的な形作りのプロセスである。種々の内的・外的撹乱により、個体発生に遅れが生じた際、その遅れを補正して正確な組織形成を実現するロバストな仕組みが存在すると考えられるが、その実体は不明である。我々は、幼虫期に顕著な発生遅延を示すショウジョウバエ<i>Minute</i>変異体(※リボソームタンパク質遺伝子の機能欠損変異をヘテロに持つ一連の変異体の総称)を起点とした解析を行った結果、幼虫期に発生遅延が起こると、その遅延を補正する「細胞ターンオーバー(細胞死と細胞増殖による細胞の入れ替え)」が翅原基で誘発されること、および、この細胞ターンオーバーが進化的に保存されたモルフォゲンWinglessの発現上昇により増幅されることを明らかにした。さらに興味深いことに、この細胞ターンオーバーを遺伝学的に抑制すると、翅脈のパターン異常や形態異常等の種々の表現型が成虫翅に出現することが分かった。これらの事実は、個体の成長遅延を補正する細胞ターンオーバー機構の偶発的なエラーが多様な表現型を出現させ得る可能性を示唆している(#Akai, #*Ohsawa (# Equal contribution, *Co-corresponding author) et al, PLoS Genetics, 2021)。今後は、個体の発生時間軸の歪みが「細胞ターンオーバー」を翅原基に誘発する機構を明らかにし、さらにはその破綻により表現型の揺らぎが生じる仕組みを明らかにすることにより、細胞集団挙動という観点から、表現型の揺らぎや生物進化の方向性を理解する新しい研究戦略を構築することを目指す。
    令和2年度が最終年度であるため、記入しない。
    令和2年度が最終年度であるため、記入しない。

  7. Robust, time-dependent coordination of tissue growth through cell-cell communications

    Grant number:19K22423  2019.6 - 2021.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Research (Exploratory)

    Ohsawa Shizue

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\6500000 ( Direct Cost: \5000000 、 Indirect Cost:\1500000 )

    Highly reproducible tissue development is achieved by robust, time-dependent coordination of cell proliferation and cell death. To study the mechanisms underlying robust tissue growth, we analyzed the developmental process of larval Drosophila Minute mutants, a series of mutants for a ribosomal protein gene, which show significantly prolonged larval period but develop into normal flies. Surprisingly, we found that both cell death and compensatory cell proliferation were dramatically increased in developing wing discs of Minute animals. Blocking the cell-turnover resulted in various morphological defects, indicating the essential role of cell-turnover in Minute wing morphogenesis. Genetic analyses showed that Minute wing discs elevate Wg expression, which cooperates with developmental delay for the induction of cell-turnover. Our findings suggest a novel paradigm for robust coordination of tissue growth by cell-turnover, which is induced when developmental time axis is distorted.

  8. genetic dissection of the intrinsic surveillance system in Drosophila epithelium

    Grant number:17H03673  2017.4 - 2020.3

    Ohsawa Shizue

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\17420000 ( Direct Cost: \13400000 、 Indirect Cost:\4020000 )

    Multicellular organisms often exert tumor suppressive mechanism that eliminates abnormal cells from the tissue. In this study, we found in the Drosophila epithelium that Slit-Robo2 repulsive signaling contributes to epithelial wound repair by promoting extrusion of dying cells from the wounded tissue caused by physical injury, which facilitates transient and appropriate induction of growth factors for proper wound healing.

  9. Virtual laboratory to accelerate international collaboration on 3D morphological logic

    Grant number:15K21726  2015.11 - 2021.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Kondo Shigeru

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    The purpose of this grant project was to make the activities of the new academic area "Logic for Constructing Three-Dimensional Morphology of Living Things" more international. The activities include dispatching young researchers to overseas conferences, holding overseas joint seminars (UC Irvine, Austria CTI, Canada TorontoUniv, Barcelona EMBL), PD stays at overseas base laboratories, and research cooperation with the University of Costa Rica. The total number of overseas joint research projects (including open calls) is 62. The number of workshops and symposia at overseas conferences organized by researchers in this field is 156 until FY2018. Invited lectures at international conferences: 50 times. The number of overseas public reports, including online news, is 17.
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    Translated with www.DeepL.com/Translator (free version)

  10. 3D morphologic

    Grant number:15H05856  2015.6 - 2020.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Kondo Shigeru

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    In the planned research in this area, we aimed to elucidate the principles of macroscopic 3D morphogenesis, which have not been addressed in previous morphogenesis research, by focusing on (1) folding and unfolding of cell sheets and (2) rotation of cell populations. In addition to the above two themes, we also adopted research related to 3D morphogenesis as open research. For both themes, we provided support in terms of equipment and opportunities for discussion so that the experimental and mathematical groups could work together smoothly. Although this was a very challenging research theme, we were able to show with actual examples that it is possible to analyze 3D morphogenesis without losing dimensions, and we believe that we were able to open up a new avenue for morphogenesis research.

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Teaching Experience (On-campus) 1

  1. 生物学基礎IIa

    2020

Teaching Experience (Off-campus) 1

  1. 生物科学特別講義

    2021.12 The University of Tokyo)

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    Level:Undergraduate (specialized)  Country:Japan

 

Social Contribution 1

  1. 愛知県立時習館高等学校 訪問説明会

    Role(s):Lecturer

    愛知県立時習館高等学校  2021.10