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Mechanisms of growth arrest-induced primary cilium formation

Research Project

Project/Area Number 18H02398
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 43030:Functional biochemistry-related
Research InstitutionTohoku University

Principal Investigator

Mizuno Kensaku  東北大学, 生命科学研究科, 名誉教授 (70128396)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Keywords一次繊毛 / ユビキチン化 / ユビキチンリガーゼ / 繊毛病 / CEP97 / CEP104 / ヘッジホッグ / YAP / 繊毛 / 細胞増殖 / 微小管 / 中心体 / Hedgehog / 細胞周期
Outline of Final Research Achievements

Primary cilia are antenna-like sensory organelles that transmit various extracellular signals. Deficits in ciliogenesis cause human disorders that are termed ciliopathies. In this project, we aimed to elucidate the mechanisms of growth arrest signal-induced ciliogenesis and obtained several findings as follows: 1) Ciliogenesis requires the removal of CEP97 from the mother centriole for initiating ciliary axoneme extension. We showed that CEP97 is degraded by the cullin-3-RBX1-KCTD10 ubiquitin ligase complex and this process is crucial for serum starvation-induced ciliogenesis. 2) CEP104 is a causative gene for Joubert syndrome. We showed that the TOG domain of CEP104 exhibits microtubule-polymerizing activity and this activity is essential for growth arrest-induced cilium elongation and Hedgehog signaling. 3) We showed that Furry suppresses nuclear localization of YAP by activating NDR1/2 kinases and directly binding to YAP.

Academic Significance and Societal Importance of the Research Achievements

一次繊毛は、多くの動物細胞が有する非運動性の繊毛で、ヘッジホッグなどの多様なシグナルを受容するアンテナとして、細胞の増殖・分化や組織の形成・恒常性維持に重要な役割を担っている。一次繊毛の形成不全は嚢胞腎、網膜変性など繊毛病とよばれる多様な疾患の原因となることが知られており、一次繊毛形成機構の解明は発生学的にも医学的にも重要な課題である。本研究では、一次繊毛形成の初期過程で重要な役割を担っているCEP97の分解機構とCEP104の微小管制御機構について新たな知見を得た。これらの成果は、一次繊毛形成の重要な機構を解明したものであり、基礎生物学の進展だけでなく医学分野にも貢献すると考えられる。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report

Research Products

(9 results)

All 2020 2019 2018 Other

All Journal Article (4 results) (of which Peer Reviewed: 4 results) Presentation (4 results) (of which Int'l Joint Research: 1 results) Remarks (1 results)

  • [Journal Article] Roles of TOG and jelly-role domains of centrosomal protein CEP104 in its functions in cilium elongation and Hedgehog signaling.2020

    • Author(s)
      Yamazoe, T., Nagai, T., Umeda, S., Sugaya, Y., and Mizuno, K.
    • Journal Title

      J. Biol. Chem.

      Volume: 295 Pages: 14723-14736

    • DOI

      10.1074/jbc.ra120.013334

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Furry protein suppresses nuclear localization of yes-associated protein (YAP) by activating NDR kinase and binding to YAP2020

    • Author(s)
      Irie, K., Nagai, T., and Mizuno, K.
    • Journal Title

      J. Biol. Chem.

      Volume: 295 Pages: 3017-3028

    • DOI

      10.1074/jbc.ra119.010783

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cullin-3-KCTD10-mediated CEP97 ubiquitination promotes primary cilium formation.2018

    • Author(s)
      Nagai, T., Mukoyama, S., Kagiwada, H., Goshima, N., and Mizuno, K.
    • Journal Title

      J. Cell Sci.

      Volume: 133

    • DOI

      10.1242/jcs.219527

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 微小管 アセチル化、脱アセチル化2018

    • Author(s)
      永井友朗、水野健作
    • Journal Title

      医学書院

      Volume: 69 (5) Pages: 484-485

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Presentation] 一次繊毛形成におけるCEP97の分解機構2019

    • Author(s)
      入江和樹、永井友朗、向山祥帆、鍵和田晴美、五島直樹、水野健作
    • Organizer
      第71回日本細胞生物学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Cullin3-KCTD10複合体によるCEP97の分解は増殖抑制依存的な一次繊毛形成を促進する2019

    • Author(s)
      永井 友朗、向山 祥帆、水野 健作
    • Organizer
      第42回日本分子生物学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 一次繊毛形成時のCEP97のユビキチン化における14-3-3タンパク質の関与2019

    • Author(s)
      入江 和樹、菅野 新一郎、永井 友朗、水野 健作
    • Organizer
      第42回日本分子生物学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Cullin3-KCTD10-mediated CEP97 degradation is crucial for serum-starvation-induced ciliogenesis.2019

    • Author(s)
      Mizuno, K.
    • Organizer
      Gordon Research Conference "Cilia, mucus and mucociliary interactions"
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Remarks] 東北大学大学院生命科学研究科 情報伝達分子解析分野

    • URL

      http://www.biology.tohoku.ac.jp/lab-www/mizuno_lab/

    • Related Report
      2018 Annual Research Report

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Published: 2018-04-23   Modified: 2022-01-27  

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