皮质激素生成
神经干细胞
神经发生
衰老
生物
细胞生物学
小头畸形
表型
祖细胞
干细胞
信号转导
SMAD公司
遗传学
基因
作者
Qing Zhu,Liping Chen,Ying Liu,Mengting Huang,Jingyuan Shao,Shen Li,Juanxian Cheng,Huanming Yang,Yan Wu,Jiyan Zhang,Jiannan Feng,Ming Fan,Haitao Wu
出处
期刊:Cell Reports
[Elsevier]
日期:2021-08-01
卷期号:36 (9): 109639-109639
被引量:13
标识
DOI:10.1016/j.celrep.2021.109639
摘要
Normal neurodevelopment relies on intricate signaling pathways that balance neural stem cell (NSC) self-renewal, maturation, and survival. Disruptions lead to neurodevelopmental disorders, including microcephaly. Here, we implicate the inhibition of NSC senescence as a mechanism underlying neurogenesis and corticogenesis. We report that the receptor for activated C kinase (Rack1), a family member of WD40-repeat (WDR) proteins, is highly enriched in NSCs. Deletion of Rack1 in developing cortical progenitors leads to a microcephaly phenotype. Strikingly, the absence of Rack1 decreases neurogenesis and promotes a cellular senescence phenotype in NSCs. Mechanistically, the senescence-related p21 signaling pathway is dramatically activated in Rack1 null NSCs, and removal of p21 significantly rescues the Rack1-knockout phenotype in vivo. Finally, Rack1 directly interacts with Smad3 to suppress the activation of transforming growth factor (TGF)-β/Smad signaling pathway, which plays a critical role in p21-mediated senescence. Our data implicate Rack1-driven inhibition of p21-induced NSC senescence as a critical mechanism behind normal cortical development.
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