Rack1 is Essential for Corticogenesis by Preventing P21-Dependent Senescence in Neural Stem Cells

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 an additional mechanism that controls 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 in the early developmental brain. Deletion of Rack1 in NSCs leads to an extreme microcephaly phenotype, including impaired corticogenesis, severe hippocampal hypoplasia, and extensive corpus callosum defects. Strikingly, the absence of Rack1 decreased neurogenesis and significantly promoted a cellular senescence phenotype in NSCs. Mechanistically, the senescence-related p21 signaling pathway was dramatically activated in Rack1-depleted NSCs, and simultaneous deletion of p21 significantly rescued the Rack1-knockout phenotype in vivo. Finally, Rack1 directly interacts with Smad3 to suppress the activation of TGF-β/Smad signaling pathway, which plays a critical role in p21-mediated senescence. Our data implicate Rack1-driven inhibition of NSC senescence as a critical mechanism behind normal cortical development. Deregulation of p21-induced senescence of NSCs may be a contributing factor in the pathology of microcephaly.