The E3 ubiquitin ligase APC / C C dh1 degrades MCPH 1 after MCPH1‐βTr CP 2‐Cdc25A‐mediated mitotic entry to ensure neurogenesis

Mutations of microcephalin ( MCPH 1) can cause the neurodevelopmental disorder primary microcephaly type 1. We previously showed that MCPH 1 deletion in neural stem cells results in early mitotic entry that distracts cell division mode, leading to exhaustion of the progenitor pool. Here, we show that MCPH 1 interacts with and promotes the E3 ligase βTr CP 2 to degrade Cdc25A independent of DNA damage. Overexpression of βTr CP 2 or the knockdown of Cdc25A remedies the high mitotic index and rescues the premature differentiation of Mcph1 ‐deficient neuroprogenitors in vivo . MCPH 1 itself is degraded by APC / C C dh1 , but not APC / C C dc20 , in late mitosis and G1 phase. Forced MCPH 1 expression causes cell death, underlining the importance of MCPH 1 turnover after mitosis. Ectopic expression of Cdh1 leads to premature differentiation of neuroprogenitors, mimicking differentiation defects of Mcph1 ‐knockout neuroprogenitors. The homeostasis of MCPH 1 in association with the ubiquitin‐proteasome system ensures mitotic entry independent of cell cycle checkpoint. This study provides a mechanistic understanding of how MCPH 1 controls neural stem cell fate and brain development.