Intracellular degradation mechanism controlling quiescence of adult neural stem cells

2019 Fiscal Year Final Research Report

• 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
• Keywords: 成体神経幹細胞 / リソソーム / 休眠状態 / TFEB

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.

Free Research Field

発生生物学

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。