Role of feedback signaling from neurons to neural stem cells in mammalian developing brain.

• Project/Area Number: 16K18381
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Shitamukai Atsunori 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, 専門職研究員 (00442971)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
• Keywords: 神経幹細胞 / ライブイメージング / 細胞内輸送 / 脳発生 / シグナル伝達 / 上皮構造 / 脳・神経 / 発生・分化

Outline of Final Research Achievements

Recently, we revealed that the inheritance of the basal process is important for the neural stem (NS) cell self-renewal. Although it is well known the basal process functions as the scaffold of migrating neurons, the role and mechanism of basal process in the controlling of NS cell self-renewal is largely unknown. Here, we showed that the basal process is critical for the receiving neuron derived FGF signal and transport of FGFR activated ERK MAPK, which promotes NS cell self-renewal. In the basal process, the activated ERK MAPK is localized on the endosomal vesicles and transported by the dynein motor system. From these results, we propose a feedback signaling system from neurons to NS cells mediated by the basal process, in which the fine tuning of proportion of neuron and NS cell number in the developing brain.

Academic Significance and Societal Importance of the Research Achievements

これまでに、神経幹細胞を維持するメカニズムは、主に細胞内因子の分配や、脳髄液から供給される増殖因子などが報告されていた。しかしながら、本研究によって、これまでの想定とは反対側の神経層からも幹細胞を維持するシグナルがあることが明らかとなり、その受容には神経細胞がが持つ構造的な特徴が重要であることが明らかとなった。これらの発見は生み出された神経細胞によって神経幹細胞がコントロールされる可能性を示唆しており、その作用メカニズムの解明は、これまで、不明でった組織内の細胞間相互作用の理解につながると予想され、組織の再生やより生体に近いオルガノイドの産生に寄与できると考えられる。

Research Products

• [Journal Article] Developing a De Novo Targeted Knock-in Method Based on in Utero Electroporation Into the Mammalian Brain (2016)
  • Author(s): Tsunekawa, Yuji, Raymond Kunikane Terhune, Ikumi Fujita, Atsunori Shitamukai, Taeko Suetsugu, Fumio Matsuzaki
  • Journal Title: Development Volume: 143 Issue: 17 Pages: 3216-3222
  • DOI: 10.1242/dev.136325
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Feedback signaling from neuron to neural stem cell. (2018)
  • Author(s): Atsunori Shitamkai, Daijiro Konno, Tomomi Shimogori, Akihiro Goto, Hiroshi Kiyonari, Shinji Takada, Michiyuki Matsuda, and Fumio Matsuzaki
  • Organizer: 22nd Biennial Meeting of the International Society of Developmental Neuroscience
  • Int'l Joint Research
• [Presentation] The radial fiber-mediated FGF signal ensures the feedback signaling from neurons to radial glial cells in the developing cerebral cortex. (2017)
  • Author(s): Atsunori Shitamkai, Daijiro Konno, Tomomi Shimogori, Akihiro Goto, Hiroshi Kiyonari, Shinji Takada, Michiyuki Matsuda, and Fumio Matsuzaki
  • Organizer: the EMBO Conference Gene Regulatory Mechanisms in Neural Fate Decisions
  • Int'l Joint Research
• [Presentation] Feedback signaling from neurons to neural stem cells (2017)
  • Author(s): Atsunori Shitamkai, Daijiro Konno, Tomomi Shimogori, Akihiro Goto, Hiroshi Kiyonari, Shinji Takada, Michiyuki Matsuda, and Fumio Matsuzaki
  • Organizer: The 4th German-Japanese Retreat on Forebrain Development
  • Int'l Joint Research
• [Presentation] 神経幹細胞のradial fiberは自己複製能維持のためのシグナル伝達分子の輸送の場として機能する (2016)
  • Author(s): 下向 敦範、今野大治郎、下郡智美、後藤明弘、高田慎治、松田道行、松崎文雄
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜、神奈川県横浜市
• [Remarks] 胎児の脳細胞に簡便に目的の遺伝子を挿入できる新技術
  • URL: http://www.cdb.riken.jp/news/2017/researches/0125_12675.html