Intracellular degradation mechanism controlling quiescence of adult neural stem cells

• Project/Area Number: 17K07409
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Developmental biology
• Research Institution: Kyoto University
• Principal Investigator: Taeko Kobayashi 京都大学, ウイルス・再生医科学研究所, 助教 (40402804)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 成体神経幹細胞 / リソソーム / 休眠状態 / TFEB / 神経幹細胞 / 細胞内分解機構

Outline of Final Research Achievements

Quiescence is important for sustaining neural stem cells (NSCs) in the adult brain over the lifespan. Lysosomes are digestive organelles that degrade membrane receptors after they undergo endolysosomal membrane trafficking. Enlarged lysosomes are present in quiescent NSCs (qNSCs) in the subventricular zone of the mouse brain, but it remains largely unknown how lysosomal function is involved in the quiescence. Here we show that qNSCs exhibit higher lysosomal activity and degrade activated EGF receptor by endolysosomal degradation more rapidly than proliferating NSCs. Chemical inhibition of lysosomal degradation in qNSCs prevents degradation of signaling receptors resulting in exit from quiescence. Furthermore, conditional knockout of TFEB, a lysosomal master regulator, delays NSCs quiescence in vitro and increases NSC proliferation in the dentate gyrus of mice. Taken together, our results demonstrate that enhanced lysosomal degradation is an important regulator of qNSC maintenance.

Academic Significance and Societal Importance of the Research Achievements

本課題では、細胞内の不要物の分解を制御しているリソソームの神経幹細胞における新たな機能を見いだした。大人の脳内には神経幹細胞が一生涯に渡って維持されていることから、その機能操作による脳疾患への治療法が着目されている。神経幹細胞におけるリソソーム機能を人為的に操作することができれば、将来、神経幹細胞の状態を脳内で制御する手法の開発が期待できる。退行性の脳疾患等へのあらたな治療法へつながる成果である。

Research Products

• [Int'l Joint Research] TIGEM(イタリア)
• [Int'l Joint Research] TIGEM(イタリア)
• [Int'l Joint Research] University of Michigan(米国)
• [Journal Article] Enhanced lysosomal degradation maintains the quiescent state of neural stem cells (2019)
  • Author(s): T. Kobayashi, W. Piao, T. Takamura, H. Kori, H. Miyachi, S. Kitano, Y. Iwamoto, M. Yamada, I. Imayoshi, S. Shioda, A. Ballabio, R. Kageyama
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 5446-5446
  • DOI: 10.1038/s41467-019-13203-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Multilayered gene control drives timely exit from the stem cell state in uncommitted progenitors during Drosophila asymmetric neural stem cell division (2018)
  • Author(s): Komori Hideyuki、Golden Krista L.、Kobayashi Taeko、Kageyama Ryoichiro、Lee Cheng-Yu
  • Journal Title: Genes & Development Volume: 32 Issue: 23-24 Pages: 1550-1561
  • DOI: 10.1101/gad.320333.118
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Lysosomal regulation of quiescence and proliferation in neural stem cells. (2020)
  • Author(s): 小林妙子
  • Organizer: German-Japanese Developmental Neuroscience Meeting 2020
  • Int'l Joint Research / Invited
• [Presentation] Lysosomal regulation of proliferation and quiescence in neural stem cells (2020)
  • Author(s): 小林妙子
  • Organizer: 第16回 成体脳ニューロン新生懇談会・「個性」創発脳共催研究会in 仙台2020（Adult Neurogenesis Meeting in Sendai 2020）
  • Invited
• [Presentation] Lysosomal regulation of proliferation and quiescence in neural stem cells (2020)
  • Author(s): 小林妙子
  • Organizer: Cell Biology, Developmental Biology and Systems Biology Course, and Faculty of Biostudy Annual Retreat.
  • Invited
• [Presentation] Enhanced lysosomal degradation in the quiescent state of neural stem cells (2018)
  • Author(s): T. Kobayashi, W. Piao, I. Imayoshi, R. Kageyama
  • Organizer: 22nd Biennial Meeting of the International Society of Developmental Neuroscience
  • Int'l Joint Research
• [Presentation] 休眠神経幹細胞におけるリソソーム機能 (2018)
  • Author(s): 小林妙子
  • Organizer: 次世代脳プロジェクト 冬のシンポジウム2018
• [Presentation] 休眠神経幹細胞におけるリソソーム機能 (2018)
  • Author(s): 小林妙子、影山龍一郎
  • Organizer: 次世代脳プロジェクト 冬のシンポジウム2018 合同若手シンポジウム
• [Presentation] The role of enhanced lysosomal degradation in quiescent neural stem cells (2018)
  • Author(s): 小林妙子
  • Organizer: International Young Scientists Workshop on Neural Development and Stem Cells
  • Int'l Joint Research / Invited
• [Presentation] 神経幹細胞の休眠状態を制御する分解機構 (2017)
  • Author(s): 小林妙子
  • Organizer: 「次世代脳」プロジェクト 冬のシンポジウム
• [Presentation] 神経幹細胞の休眠状態を制御する分解機構 (2017)
  • Author(s): 小林妙子
  • Organizer: 「脳構築の時計と場」「スクラップビルド」合同若手シンポジウム
• [Remarks] リソソームが成体神経幹細胞を制御するメカニズムを解明
  • URL: https://www.infront.kyoto-u.ac.jp/achievements/post-5012/
• [Remarks] リソソームが成体神経幹細胞を制御するメカニズムを解明
  • URL: http://www.kyoto-u.ac.jp/ja/research/research_results/2019/191129_1.html
• [Remarks] リソソームが成体神経幹細胞を制御するメカニズムを解明
  • URL: https://www.amed.go.jp/news/release_20191129-02.html