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Significance and molecular mechanisms of primary cilia controlling the stress critical period of cortical development.

Research Project

Project/Area Number 19K07829
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 51030:Pathophysiologic neuroscience-related
Research InstitutionKeio University

Principal Investigator

ISHII Seiji  慶應義塾大学, 医学部(信濃町), 助教 (50468493)

Project Period (FY) 2019-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords大脳皮質 / 一次繊毛 / 環境ストレス / アルコール / 麻酔薬 / 細胞外小胞 / 樹状突起 / アルコール曝露 / 環境ストレ ス
Outline of Research at the Start

一次繊毛は、マウス大脳皮質の神経細胞において、胎生期にはまだ殆ど存在せず、出生後、ストレス耐性の臨界期が終了する頃までに成熟することが知られている。これまでの結果から、臨界期後に、一次繊毛の出現に依存して誘導されるストレス応答シグナルとしてIGF1-Akt経路が考えられ、この経路の活性化が、神経細胞が環境ストレスに対する抵抗性を獲得する一因となっている可能性が考えられる。そこで、環境ストレス下での一次繊毛を介したIGF1-Aktシグナル活性化の解析を行い、ストレス応答に対する臨界期の概念、及びその動的変化を制御する分子基盤を確立することを本研究の目的とする。

Outline of Final Research Achievements

It has been suggested that there is a "critical period" in mouse cortical neurons immediately after birth, when they become vulnerable to environmental stress. On the other hand, primary cilia are still largely absent in neurons of the mouse cerebral cortex during the embryonic period, and are known to mature by the end of the critical period for stress tolerance after birth. Layer 5 neurons in the cerebral cortex of mice lacking primary cilia that had been exposed to environmental stress on postnatal day 7 was examined and found that speckled active caspase-3 was detected in large numbers, especially in layer 5 neurons of the cerebral cortex. They also found that IGF-1 receptors accumulated on the primary ciliary membranes of neurons in the cerebral cortex and activated the PI3K/Akt signaling pathway.

Academic Significance and Societal Importance of the Research Achievements

一次繊毛の形成、機能異常に起因すると考えられている遺伝性疾患は総称して繊毛病(シリオパチー)と呼ばれ、網膜色素変性症、嚢胞腎、多指症、水頭症、不妊、肥満など、多岐にわたる症状を呈することが知られている。本研究において「環境ストレスに対する一次繊毛を介した臨界期中枢神経系の防御機構」の分子基盤を明らかにする事で、一次繊毛を介した環境ストレス応答機構という新たな概念を提唱することができ、一次繊毛に対する理解が深まるものと期待される。本研究において得られた知見は、今後、多岐にわたる繊毛病の発症メカニズムの理解や新たな治療法への応用に貢献できるものと考えられる。

Report

(5 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (10 results)

All 2023 2022 2020 2019 Other

All Journal Article (7 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 5 results,  Open Access: 4 results) Presentation (1 results) (of which Invited: 1 results) Remarks (2 results)

  • [Journal Article] Caspase-3 inhibition toward perinatal protection of the developing brain from environmental stress2023

    • Author(s)
      Kaji Anna Arjun、Torii Masaaki、Ishii Seiji
    • Journal Title

      Developmental Neuroscience

      Volume: - Issue: 2 Pages: 66-75

    • DOI

      10.1159/000529125

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The elucidation of environmental stress-resistant mechanism generated by primary cilia in the cerebral cortex2022

    • Author(s)
      石井 聖二
    • Journal Title

      生化学

      Volume: 94 Issue: 1 Pages: 118-121

    • DOI

      10.14952/SEIKAGAKU.2022.940118

    • ISSN
      0037-1017
    • Year and Date
      2022-02-25
    • Related Report
      2021 Research-status Report
  • [Journal Article] A next-generation iPSC-derived forebrain organoid model of tauopathy with tau fibrils by AAV-mediated gene transfer2022

    • Author(s)
      Shimada Hiroko、Sato Yuta、Sasaki Takashi、Shimozawa Aki、Imaizumi Kent、Shindo Tomoko、Miyao Sachiyo、Kiyama Kosuke、Kondo Takahiro、Shibata Shinsuke、Ishii Seiji、Kuromitsu Junro、Aoyagi Hirofumi、Ito Daisuke、Okano Hideyuki
    • Journal Title

      Cell Reports Methods

      Volume: 2 Issue: 9 Pages: 100289-100289

    • DOI

      10.1016/j.crmeth.2022.100289

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Kcnn2 blockade reverses learning deficits in a mouse model of fetal alcohol spectrum disorders2020

    • Author(s)
      Mohammad Shahid、Page Stephen J.、Wang Li、Ishii Seiji、Li Peijun、Sasaki Toru、Basha Aiesha、Salzberg Anna、Quezado Zenaide、Imamura Fumiaki、Nishi Hirotaka、Isaka Keiichi、Corbin Joshua G.、Liu Judy S.、Kawasawa Yuka Imamura、Torii Masaaki、Hashimoto-Torii Kazue
    • Journal Title

      Nature Neuroscience

      Volume: 23 Issue: 4 Pages: 533-543

    • DOI

      10.1038/s41593-020-0592-z

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Dual Role of Rbpj in the Maintenance of Neural Progenitor Cells and Neuronal Migration in Cortical Development2020

    • Author(s)
      Son Alexander I、Mohammad Shahid、Sasaki Toru、Ishii Seiji、Yamashita Satoshi、Hashimoto-Torii Kazue、Torii Masaaki
    • Journal Title

      Cerebral Cortex

      Volume: 30 Issue: 12 Pages: 6444-6457

    • DOI

      10.1093/cercor/bhaa206

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Primary cilia safeguard cortical neurons in neonatal mouse forebrain from environmental stress-induced dendritic degeneration2020

    • Author(s)
      Ishii Seiji、Sasaki Toru、Mohammad Shahid、Hwang Hye、Tomy Edwin、Somaa Fahad、Ishibashi Nobuyuki、Okano Hideyuki、Rakic Pasko、Hashimoto-Torii Kazue、Torii Masaaki
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 118 Issue: 1 Pages: 1-10

    • DOI

      10.1073/pnas.2012482118

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Environmental stress impacts the developing brain2019

    • Author(s)
      Ishii Seiji
    • Journal Title

      Impact

      Volume: 2019 Issue: 7 Pages: 23-25

    • DOI

      10.21820/23987073.2019.7.23

    • Related Report
      2019 Research-status Report
    • Open Access
  • [Presentation] 大脳皮質の一次繊毛が生み出す環境ストレス耐性機構2022

    • Author(s)
      石井 聖二
    • Organizer
      第127回 日本解剖学会総会・全国学術集会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Remarks] 慶應義塾大学プレスリリース (次世代型認知症モデル脳オルガノイドの作製に成功)

    • URL

      https://www.keio.ac.jp/ja/press-releases/2022/9/9/28-131824/

    • Related Report
      2022 Annual Research Report
  • [Remarks] 慶應義塾大学プレスリリース (一次繊毛が生み出す環境ストレス耐性機構の解明)

    • URL

      https://www.keio.ac.jp/ja/press-releases/2021/1/6/28-77297/

    • Related Report
      2020 Research-status Report

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Published: 2019-04-18   Modified: 2024-01-30  

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