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Physiological significance of ultradian oscillatory gene expression

Research Project

Project/Area Number 21H04976
Research Category

Grant-in-Aid for Specially Promoted Research

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionInstitute of Physical and Chemical Research

Principal Investigator

影山 龍一郎  国立研究開発法人理化学研究所, 生命機能科学研究センター, センター長 (80224369)

Co-Investigator(Kenkyū-buntansha) 磯村 彰宏  国立研究開発法人理化学研究所, 生命機能科学研究センター, 研究員 (70512466)
大塚 俊之  京都大学, ウイルス・再生医科学研究所, 准教授 (20324709)
Project Period (FY) 2021-05-18 – 2026-03-31
Project Status Granted (Fiscal Year 2025)
Budget Amount *help
¥596,180,000 (Direct Cost: ¥458,600,000、Indirect Cost: ¥137,580,000)
Fiscal Year 2025: ¥117,000,000 (Direct Cost: ¥90,000,000、Indirect Cost: ¥27,000,000)
Fiscal Year 2024: ¥117,000,000 (Direct Cost: ¥90,000,000、Indirect Cost: ¥27,000,000)
Fiscal Year 2023: ¥117,000,000 (Direct Cost: ¥90,000,000、Indirect Cost: ¥27,000,000)
Fiscal Year 2022: ¥130,000,000 (Direct Cost: ¥100,000,000、Indirect Cost: ¥30,000,000)
Fiscal Year 2021: ¥115,180,000 (Direct Cost: ¥88,600,000、Indirect Cost: ¥26,580,000)
Keywords神経幹細胞 / 発現振動 / Hes1 / 光遺伝学 / 細胞周期 / 短周期発現振動 / Tbr2 / Neurog2 / 中間前駆細胞 / サイクリン依存性キナーゼ阻害因子 / p21 / Erk / Dusp7 / 短周期振動 / 振動遺伝子 / 神経発生 / 生物時計 / Ascl1 / Plagl2 / anti-Dyrk1a / 若返り / 成体脳ニューロン新生 / 認知機能
Outline of Research at the Start

多くの生命活動で遺伝子発現が数時間という短周期で振動するが、その生理学的意義には不明の点が多い。神経発生過程では転写抑制因子Hes1の発現は自律的に短周期振動し、Hes1によって周期的に抑制されて他の遺伝子発現も振動する。この振動が抑制されると神経発生に異常が起こるが、短周期振動によって起こる現象の詳細は不明である。本研究では短周期振動の上流や下流を詳細に解析し、短周期振動の生理学的意義を解明する。

Outline of Annual Research Achievements

神経発生過程の初期には対称分裂によって1個の神経幹細胞は2個の神経幹細胞になり細胞数が増加するが、発生期の途中から非対称分裂によって1個の神経幹細胞から1個の神経幹細胞と1個の中間前駆細胞に分かれる。中間前駆細胞は数回分裂して数個のニューロンを生み出す。神経幹細胞ではHes1の発現が振動するが、中間前駆細胞ではHes1は発現していない。対称分裂か非対称分裂かの選択がどのように制御されるのかを調べた。
神経幹細胞ではHes1の発現振動によって周期的に抑制されるため、プロニューラル遺伝子Neurog2の発現も振動する。その下流因子を解析したところ、Tbr2の発現が徐々に上昇してHes1の発現を抑制し、その後、神経幹細胞が非対称分裂した。一方、Tbr2のKOマウスでは神経幹細胞におけるHes1の発現が増加し、中間前駆細胞の形成が顕著に減少した。したがって、非対称分裂する前の神経幹細胞では、Tbr2の発現が蓄積してHes1の発現が抑制されていることから、中間前駆細胞の状態になっていることが明らかになった。
神経幹細胞は多分化能を持つのに対して中間前駆細胞はニューロン分化能のみを持つ。また、両者の細部は形態的にも全く異なる。したがって、神経幹細胞から中間前駆細胞への分化過程は不連続である。しかし、最近の1細胞RNA配列解析から、神経幹細胞から中間前駆細胞への分化過程では遺伝子発現パターンが連続的に変化することが知られていた。この不一致性の原因はよく分かっていなかったが、本研究により、神経幹細胞内で遺伝子発現パターンが連続的に中間前駆細胞様まで変化することが明らかになった。また、この結果から、Hes1のパルス数は非対称分裂開始のタイマーの役割を担うことが示唆された。

Current Status of Research Progress
Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

Hes1の発現振動でプロニューラル遺伝子Neurog2の発現が振動し、その下流因子の発現が徐々に蓄積してHes1の発現を抑制することで神経幹細胞が非対称分裂するということを見出し、Hes1やNeurog2のパルス数によって神経分化が開始するというタイマー機能を明らかにした。本成果は、近く論文として発表予定であり、研究は順調に進展している。

Strategy for Future Research Activity

神経幹細胞に光遺伝学的Hes1発現誘導システムを導入し、Hes1の発現を2時間周期で同期振動させて経時的にトランスクリプトーム解析を行ったところ、Hes1と同期振動する417遺伝子の同定に成功した。この中に多くの細胞周期関連遺伝子が含まれていた。既にHes1の発現動態が振動か持続かでp21の発現抑制あるいは発現増加を誘導し、神経幹細胞の増殖を活性化あるいは抑制化することを明らかにしたが、p21以外の多くの細胞周期関連遺伝子がHes1によって発現振動することが分かってきたので、細胞周期における短周期振動の意義についてさらに詳細に解析する。

Assessment Rating
Interim Assessment Comments (Rating)

A: In light of the aim of introducing the research area into the research categories, the expected progress has been made in research.

Report

(7 results)
  • 2023 Abstract (Interim Assessment) ( PDF )   Annual Research Report   Interim Assessment (Comments) ( PDF )
  • 2022 Annual Research Report
  • 2021 Abstract ( PDF )   Comments on the Screening Results ( PDF )   Annual Research Report
  • Research Products

    (45 results)

All 2024 2023 2022 2021 Other

All Int'l Joint Research (11 results) Journal Article (11 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 11 results,  Open Access: 6 results) Presentation (16 results) (of which Int'l Joint Research: 16 results,  Invited: 16 results) Remarks (4 results) Patent(Industrial Property Rights) (2 results) (of which Overseas: 2 results) Funded Workshop (1 results)

  • [Int'l Joint Research] University of California/Harvard University(米国)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] University of Algarve(ポルトガル)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Maastricht University(オランダ)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Federal University of Santa Catarina(ブラジル)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] University of Heidelberg(ドイツ)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] University of Toronto(カナダ)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] Salk Institute for Biological Studies/University of California(米国)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] European Molecular Biology Laboratory(スペイン)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] Universidade do Algarve(ポルトガル)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] Max-Delbrueck-Centrum(ドイツ)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] National Institutes of Health(米国)

    • Related Report
      2021 Annual Research Report
  • [Journal Article] SUMOylation effects on neural stem cells self-renewal, differentiation, and survival2024

    • Author(s)
      Queiroz Leticia Yoshitome、Kageyama Ryoichiro、Cimarosti Helena I.
    • Journal Title

      Neuroscience Research

      Volume: 199 Pages: 1-11

    • DOI

      10.1016/j.neures.2023.09.006

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Fluctuation of lysosomal protein degradation in neural stem cells of the postnatal mouse brain2024

    • Author(s)
      Zhang He、Ishii Karan、Shibata Tatsuya、Ishii Shunsuke、Hirao Marika、Lu Zhou、Takamura Risa、Kitano Satsuki、Miyachi Hitoshi、Kageyama Ryoichiro、Itakura Eisuke、Kobayashi Taeko
    • Journal Title

      Development

      Volume: 151 Issue: 4

    • DOI

      10.1242/dev.202231

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Transcriptional control of neural stem cell activity2024

    • Author(s)
      Kaise Takashi、Kageyama Ryoichiro
    • Journal Title

      Biochemical Society Transactions

      Volume: 52 Issue: 2 Pages: 617-626

    • DOI

      10.1042/bst20230439

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The significance of ultradian oscillations in development2024

    • Author(s)
      Maeda Yuki、Kageyama Ryoichiro
    • Journal Title

      Current Opinion in Genetics and Development

      Volume: 86 Pages: 102180-102180

    • DOI

      10.1016/j.gde.2024.102180

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The Neurog2-Tbr2 axis forms a continuous transitions to the neurogenic gene expression state in neural stem cells2024

    • Author(s)
      Shimojo Hiromi, Masaki Taimu, Kageyama Ryoichiro
    • Journal Title

      Developmental Cell

      Volume: -

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Differential cell-cycle control by oscillatory versus sustained Hes1 expression via p212023

    • Author(s)
      Maeda Yuki、Isomura Akihiro、Masaki Taimu、Kageyama Ryoichiro
    • Journal Title

      Cell Reports

      Volume: 42 Issue: 5 Pages: 112520-112520

    • DOI

      10.1016/j.celrep.2023.112520

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Biological Significance of the Coupling Delay in Synchronized Oscillations2023

    • Author(s)
      Kageyama Ryoichiro、Isomura Akihiro、Shimojo Hiromi
    • Journal Title

      Physiology

      Volume: 38 Issue: 2 Pages: 63-72

    • DOI

      10.1152/physiol.00023.2022

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Modification of gene expression and soluble factor secretion in the lateral ventricle choroid plexus: Analysis of the impacts on the neocortical development2022

    • Author(s)
      Kinoshita Akira、Shqirat Mohammed、Kageyama Ryoichiro、Ohtsuka Toshiyuki
    • Journal Title

      Neuroscience Research

      Volume: 177 Pages: 38-51

    • DOI

      10.1016/j.neures.2021.12.005

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Time-Lapse Bioluminescence Imaging of Hes7 Expression In Vitro and Ex Vivo2022

    • Author(s)
      Sanaki-Matsumiya Marina、Kageyama Ryoichiro
    • Journal Title

      Methods Mol Biol

      Volume: 2525 Pages: 321-332

    • DOI

      10.1007/978-1-0716-2473-9_25

    • ISBN
      9781071624722, 9781071624739
    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 25 years of the segmentation clock gene2022

    • Author(s)
      Kageyama Ryoichiro
    • Journal Title

      Nature

      Volume: 611 Issue: 7937 Pages: 671-673

    • DOI

      10.1038/d41586-022-03562-2

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Functional rejuvenation of aged neural stem cells by Plagl2 and anti-Dyrk1a activity2022

    • Author(s)
      Kaise Takashi、Fukui Masahiro、Sueda Risa、Piao Wenhui、Yamada Mayumi、Kobayashi Taeko、Imayoshi Itaru、Kageyama Ryoichiro
    • Journal Title

      Genes & Development

      Volume: 36 Issue: 1-2 Pages: 23-37

    • DOI

      10.1101/gad.349000.121

    • NAID

      120007185924

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Dynamic transcriptional control of active versus quiescent neural stem cells2024

    • Author(s)
      Ryoichiro Kageyama
    • Organizer
      3rd Neurogenesis Conference in Cancun
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Dynamic trnascriptional control of active versus quiescent neural stem cells2023

    • Author(s)
      Ryoichiro Kageyama
    • Organizer
      Cold Spring Harbor Laborarory Symposium
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Imaging and quantitative analysis of synchronized Hes7 oscillations in the mouse segmentation clock2023

    • Author(s)
      Ryoichiro Kageyama
    • Organizer
      International Society for Stem Cell Research Annual Meeting
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Dynamic trnascriptional control of neural stem cells2023

    • Author(s)
      Ryoichiro Kageyama
    • Organizer
      日本神経科学会大会
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Regulatory mechanisms of proliferation and differentiation of neural stem cells2023

    • Author(s)
      Ryoichiro Kageyama
    • Organizer
      EMBO Workshop
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Imaging and quantitative analysis of synchronized Hes7 oscillations in the mouse segmentation clock2023

    • Author(s)
      Ryoichiro Kageyama
    • Organizer
      Notch meeting
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Functional rejuvenation of aged neural stem cells2022

    • Author(s)
      Ryoichiro Kageyama
    • Organizer
      24th Biennial Meeting of the International Society for Developmental Neuroscience
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Imaging and quantitative analysis of synchronized Hes7 oscillations in the mouse segmentation clock2022

    • Author(s)
      Ryoichiro Kageyama
    • Organizer
      Janelia Research Conference: Imaging Mouse Development
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Dynamic transcriptional control of active versus quiescent neural stem cells2022

    • Author(s)
      Ryoichiro Kageyama
    • Organizer
      Development Workshop: Cell state transitions
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Dynamic transcriptional control of active versus quiescent neural stem cells2022

    • Author(s)
      Ryoichiro Kageyama
    • Organizer
      Closing Conference: Maintenance and differentiation of stem cells in development and disease
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Dynamic transcriptional control of active versus quiescent neural stem cells2022

    • Author(s)
      Ryoichiro Kageyama
    • Organizer
      19th International Congress of Developmental Biology
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Roles of Hes1 oscillations in neural stem cells2022

    • Author(s)
      Ryoichiro Kageyama
    • Organizer
      EMBO | EMBL Symposium: Biological oscillators: design, mechanism, function
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Functional rejuvenation of aged neural stem cells by Plagl2 and anti-Dyrk1a activity2022

    • Author(s)
      Ryoichiro Kageyama
    • Organizer
      The International Symposium on Development and Plasticity of Neural Systems
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Dynamic control of neural stem cells in the adult brain.2021

    • Author(s)
      Ryoichiro Kageyama
    • Organizer
      ABC-RI International Forum-Neuroscience in Health and Disease, Lisbon, Portugal
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Dynamic control of neural stem cells2021

    • Author(s)
      Ryoichiro Kageyama
    • Organizer
      ASHBi Symposium, Kyoto
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Dynamic transcriptional control regulates active versus quiescent neural stem cells2021

    • Author(s)
      Ryoichiro Kageyama
    • Organizer
      The 16th International Symposium of the Institute Network for Biomedical Sciences, Kumamoto
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Remarks] 神経幹細胞の活性状態と休眠状態を制御する仕組み

    • URL

      https://www.riken.jp/press/2023/20230531_2/index.html

    • Related Report
      2023 Annual Research Report
  • [Remarks] 老化する脳を若返らせる -- 神経幹細胞の活性化と記憶力回復

    • URL

      https://www.youtube.com/watch?v=h5ciNou5XKo

    • Related Report
      2023 Annual Research Report
  • [Remarks] 神経幹細胞研究チーム

    • URL

      https://cbs.riken.jp/jp/faculty/r.kageyama/index.html

    • Related Report
      2022 Annual Research Report
  • [Remarks] 老化神経幹細胞の若返りによるニューロン産生の復活と認知機能の改善

    • URL

      https://www.kyoto-u.ac.jp/ja/research-news/2021-12-17

    • Related Report
      2021 Annual Research Report
  • [Patent(Industrial Property Rights)] A NEW METHOD FOR ACTIVATION OF ADULT NEUROGENESIS AND REDUCTION OF AMYLOID-B DEPOSITION2023

    • Inventor(s)
      R. Kageyama, M. Fukui
    • Industrial Property Rights Holder
      R. Kageyama, M. Fukui
    • Industrial Property Rights Type
      特許
    • Filing Date
      2023
    • Related Report
      2023 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] 神経変性疾患治療のためのポリヌクレオチド、ベクター、細胞、医薬組成物及びスクリーニング法2022

    • Inventor(s)
      影山龍一郎、貝瀬峻、福井雅弘
    • Industrial Property Rights Holder
      影山龍一郎、貝瀬峻、福井雅弘
    • Industrial Property Rights Type
      特許
    • Filing Date
      2022
    • Related Report
      2021 Annual Research Report
    • Overseas
  • [Funded Workshop] International Symposium on Neural Development & Diseases2023

    • Related Report
      2022 Annual Research Report

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Published: 2021-05-21   Modified: 2025-06-20  

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