Physiological roles and action mechanisms of mDia-induced actin cytoskeleton in the body

• Project/Area Number: 26221302
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: General medical chemistry
• Research Institution: Kyoto University
• Principal Investigator: Narumiya Shuh 京都大学, 医学研究科, 教授 (70144350)
• Co-Investigator(Kenkyū-buntansha): 石崎 敏理 大分大学, 医学部, 教授 (70293876)
• Project Period (FY): 2014-05-30 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥172,120,000 (Direct Cost: ¥132,400,000、Indirect Cost: ¥39,720,000); Fiscal Year 2016: ¥49,400,000 (Direct Cost: ¥38,000,000、Indirect Cost: ¥11,400,000); Fiscal Year 2015: ¥49,400,000 (Direct Cost: ¥38,000,000、Indirect Cost: ¥11,400,000); Fiscal Year 2014: ¥73,320,000 (Direct Cost: ¥56,400,000、Indirect Cost: ¥16,920,000)
• Keywords: アクチン / Rho / mDia / シナプス / T細胞 / 精子形成 / 皮膚腫瘍 / 神経可塑性 / T 細胞 / 皮膚がん化 / TCRシグナリング / 腫瘍形成 / アクチン細胞骨格 / 細胞悪性化

Outline of Final Research Achievements

While the actin cytoskeleton plays an important role in cell morphogenesis, adhesion,migration and division,its role in various body functions remains largely obscure.In this study we examined this issue by generating KO mice deficient in mDia, an actin polymerizing factor, and analyzing their phenotypes in the brain, the immune system, the reproductive system and tumorigenesis. In the brain, mDia-induced actin cytoskeleton is critically involved in synaptic remodeling that is required for social isolation-induced elevated anxiety. mDia-induced actin cytoskeleton is also involved in T cell activation by regulating dynamics of antigen-bound T cell receptors, morphogenesis of sperm by regulating interaction between germ cells and Sertoli cells in the testis and malignant cell transformation and tumorigenesis by interaction with Ras in chemical carcinogenesis model in the skin.

Assessment Rating

Verification Result (Rating)

A-

Result (Rating)

A-: Progress in the research is steadily towards the initial goal. However, further efforts are necessary as a part of the research progress is delayed.

Research Products

• [Journal Article] mDia and ROCK mediate actin-dependent presynaptic remodeling regulating synaptic efficacy and anxiety. (2016)
  • Author(s): Deguchi Y, Harada M, Shinohara R, Lazarus M, Cherasse Y, Urade Y, Yamada D, Sekiguchi M, Watanabe D, Furuyashiki T, Narumiya S.
  • Journal Title: Cell Rep. Volume: 17 Pages: 24052417-24052417
  • DOI: 10.1016/j.celrep.2016.10.088
  • NAID: 120005954512
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] PI3K regulates endocytosis after insulin secretion by mediating signaling crosstalk between Arf6 and Rab27a (2016)
  • Author(s): Yamaoka M, Ando T, Terabayashi T, Okamoto M, Takei M, Nishioka T, Kaibuchi K, Matsunaga K, Ishizaki R, Izumi T, Niki I, Ishizaki T, Kimura T
  • Journal Title: J. Cell Sci. Volume: 129 Pages: 637-649
  • DOI: 10.1242/jcs.180141
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 免疫シナプスにおけるmDia1/3依存的なF-actinの機能解析 (2017)
  • Author(s): 桂善親、タムケオ ディーン、成宮周
  • Organizer: 第90回 日本薬理学会年会
  • Place of Presentation: 長崎：長崎パブリックホール
  • Year and Date: 2017-03-17
• [Presentation] 目の発生におけるmDiaの機能解析 (2017)
  • Author(s): タムケオ ディーン、坂本智子、符毅欣、成宮周
  • Organizer: 第90回 日本薬理学会年会
  • Place of Presentation: 長崎：長崎パブリックホール
  • Year and Date: 2017-03-17
• [Presentation] 精子形成におけるmDia1/3の機能解析 (2017)
  • Author(s): 符毅欣、坂本智子、タムケオ ディーン、成宮周
  • Organizer: 第90回 日本薬理学会年会
  • Place of Presentation: 長崎：長崎パブリックホール
  • Year and Date: 2017-03-17
• [Presentation] Role of Rho-mDia1 Signaling in the Pressure Overload-Induced Cardiac Hypertrophic Response (2017)
  • Author(s): Ichitaro Abe, Y Teshima, Y Yonehara, H Kaku, S Kira,T Oniki, Y Ikebe, H Kondo, S Saito, T Terabayashi, T Ishizaki, Naohiko Takahashi
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 金沢：石川県立音楽堂
  • Year and Date: 2017-03-17
• [Presentation] 心肥大応答におけるmDiaの役割 (2016)
  • Author(s): 安部一太郎、手嶋泰之、寺林健、石崎敏理、髙橋尚彦
  • Organizer: 第26回日本病態生理学会
  • Place of Presentation: 金沢: 金沢医科大学
  • Year and Date: 2016-08-05
• [Presentation] Indispensable role of mDia1/3 in sperm morphogenesis through the remodeling of Sertoli cell meshwork F-actin (2016)
  • Author(s): タムケオ ディーン、坂本智子、成宮周
  • Organizer: 第89回日本薬理学会
  • Place of Presentation: 横浜市
  • Year and Date: 2016-03-10
• [Presentation] Regulation of cortical F-actin meshwork architecture in Sertoli cell by mDia1/3 (2016)
  • Author(s): タムケオ ディーン、坂本智子、成宮周
  • Organizer: 生体運動合同班会議
  • Place of Presentation: 京都市
  • Year and Date: 2016-01-08
• [Presentation] Roles of mDia1/3 in neuroepithelium integrity and neuroblast migration (2015)
  • Author(s): Dean Thumkeo, Ryota Shinohara, Shuh Narumiya
  • Organizer: The 56th Annual Meeting of the American Society for Cell Biology
  • Place of Presentation: San Diego, USA
  • Year and Date: 2015-12-14
  • Int'l Joint Research
• [Presentation] 膵B細胞におけるエンドサイトーシスの時間的・空間的制御機構の解析 (2015)
  • Author(s): 山岡真美、寺林健、松永耕一、泉哲郎、仁木一郎、石崎敏理、木村俊秀
  • Organizer: 第38回日本分子生物学会年会
  • Place of Presentation: 神戸市
  • Year and Date: 2015-12-01
• [Presentation] マウス社会隔離ストレスによる不安亢進とシナプス前終末可塑性におけるRho制御アクチン重合因子mDiaの役割 (2015)
  • Author(s): 出口 雄一
  • Organizer: 生理学研究所研究会『情動研究会』「感覚刺激・薬物による快・不快情動生成機構とその破綻」
  • Place of Presentation: 岡崎市
  • Year and Date: 2015-10-07
  • Invited
• [Presentation] マウス社会隔離ストレスによる不安亢進とシナプス前終末可塑性とにおけるRho制御アクチン重合因子mDiaの役割 (2015)
  • Author(s): 出口 雄一
  • Organizer: 第45回日本神経精神薬理学会、第37回日本生物学的精神医学会、合同年会
  • Place of Presentation: 東京都
  • Year and Date: 2015-09-26
• [Presentation] mDia1/3-mediated cortical F-actin assembly is required for T cell receptor signaling (2015)
  • Author(s): Dean Thumkeo, Kiyoshi Tohyama, Pakorn Kanchanawong, Shuh Narumiya
  • Organizer: 第67回日本細胞生物学会
  • Place of Presentation: 東京都
  • Year and Date: 2015-07-02
• [Presentation] 精子形成におけるRho標的タンパク質・フォルミンファミリーアクチン核化因子mDiaの役割解明 (2015)
  • Author(s): 坂本智子、タムケオ ディーン、伊川正人、藤原祥高、大田浩、渡邉定則、成宮周
  • Organizer: 第67回日本細胞生物学会
  • Place of Presentation: 東京都
  • Year and Date: 2015-07-02
• [Presentation] 膵B細胞におけるエンドサイトーシスの時間的・空間的制御機構の解析 (2015)
  • Author(s): 山岡真美、安藤朋海、寺林健、松永耕一、泉哲郎、仁木一郎、石崎敏理、木村俊秀
  • Organizer: 第58回日本糖尿病学会年次学術集会
  • Place of Presentation: 山口市
  • Year and Date: 2015-05-21
• [Presentation] Formin family actin nucleators, mDia1 and mDia3, mediate TCR microcluster dynamics and signaling critical for positive selection of thymocytes. (2015)
  • Author(s): Thumkeo, D., Nomachi, A., Tohyama, K., and Narumiya, S.
  • Organizer: The 88th Annual Meeting of the Japanese Pharmacological Society.
  • Place of Presentation: Nagoya, Japan
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] T cell cortical F-actin is mediated by mDia and critical for TCR signaling. (2015)
  • Author(s): Tohyama, K., Thumkeo, D., and Narumiya, S.
  • Organizer: The 88th Annual Meeting of the Japanese Pharmacological Society.
  • Place of Presentation: Nagoya, Japan
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] mDia1 and mDia3, formin family actin nucleators and Rho effectors, mediate TCR microcluster dynamics and signaling and are critical for positive selection of thymocytes. (2014)
  • Author(s): Narumiya, S., Thumkeo, D., Beemiller, O. and Krummel, M.F.
  • Organizer: The 2014 Cold Spring Harbor Asia Conference on “GTPases: Mechanisms, interactions and applications”
  • Place of Presentation: Suzhou, China
  • Year and Date: 2014-09-22 – 2014-09-26
  • Invited
• [Presentation] A role for mDia, a Rho-regulated actin nucleator, in chronic stress-induced behavioral changes and synaptic plasticity. (2014)
  • Author(s): Deguchi, Y., Harada, M., Shinohara, R., Watanave, D., Furuyashiki, T., and Narumiya, S.
  • Organizer: The 2014 Cold Spring Harbor Asia Conference on “GTPases: Mechanisms, interactions and applications”
  • Place of Presentation: Suzhou, China
  • Year and Date: 2014-09-22 – 2014-09-26
• [Presentation] A role for mDia, a Rho-regulated actin nucleator, in chronic stress-induced behavioral changes and synaptic plasticity. (2014)
  • Author(s): Deguchi, Y., Harada, M., Shinohara, R., Lazarus, M., Cherasse, Y., Urade, Y., Watanabe, D., Furuyashiki, T., and Narumiya, S.
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: Yokohama, Japan
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] A role for mDia, a Rho-regulated actin nucleator, in regulating morphology of presynaptic terminals and increased anxiety-like behavior induced by social isolation stress in mice. (2014)
  • Author(s): Deguchi, Y., Harada, M., Shinohara, R., Lazarus, M., Cherasse, Y., Urade, Y., Watanabe, D., Furuyashiki T., and Narumiya, S.
  • Organizer: The 88th Annual Meeting of the Japanese Pharmacological Society
  • Place of Presentation: Nagoya, Japan
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Indispensable role of formin family actin nucleator, mDia1 and mDia3, in TCR microcluster dynamics and signaling critical for positive selection of thymocytes. (2014)
  • Author(s): Thumkeo, D., Beemiller, P., Nomachi, A., Krummel, M.F. and Narumiya, S.
  • Organizer: The 37th Naito Conference “Bioimaging-a paradigm shift for the life science”.
  • Place of Presentation: Niseko, Hokkaido, Japan
  • Year and Date: 2014-07-15 – 2014-07-18
• [Presentation] Role of mDia in Spermatogenesis. (2014)
  • Author(s): Sakamoto, S., Thumkeo, D., and Narumiya, S.
  • Organizer: he 66th Annual Meeting of the Japanese Society for Cell Biology.
  • Place of Presentation: Nara, Japan
  • Year and Date: 2014-06-11 – 2014-06-13
• [Presentation] The formin protein mDia is indispensible for TCR signaling dependent T cell development through actin nucleation activity. (2014)
  • Author(s): Thumkeo, D., Beemiller, P., Nomachi, A., Krummel, M.F. and Narumiya, S.
  • Organizer: The 66th Annual Meeting of the Japanese Society for Cell Biology
  • Place of Presentation: Nara, Japan
  • Year and Date: 2014-06-11 – 2014-06-13
• [Book] Molecular structures, cellular functions, and physiological roles of Rho effectors in Ras Superfamily Small G Proteins: Biology and Mechanisms (ed. Alfred Wittinghofer) (2014)
  • Author(s): Ishizaki T and Narumiya S
  • Total Pages: 742
  • Publisher: Springer