| First Author | Zhu Q | Year | 2021 |
| Journal | Cell Rep | Volume | 36 |
| Issue | 9 | Pages | 109639 |
| PubMed ID | 34469723 | Mgi Jnum | J:310644 |
| Mgi Id | MGI:6764024 | Doi | 10.1016/j.celrep.2021.109639 |
| Citation | Zhu Q, et al. (2021) Rack1 is essential for corticogenesis by preventing p21-dependent senescence in neural stem cells. Cell Rep 36(9):109639 |
| abstractText | 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)-beta/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. |
