The E3 ubiquitin ligase APC/CCdh1 degrades MCPH1 after MCPH1‐βTrCP2‐Cdc25A‐mediated mitotic entry to ensure neurogenesis

Mutations of microcephalin (MCPH1) can cause the neurodevelopmental disorder primary microcephaly type 1. We previously showed that MCPH1 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 MCPH1 interacts with and promotes the E3 ligase βTrCP2 to degrade Cdc25A independent of DNA damage. Overexpression of βTrCP2 or the knockdown of Cdc25A remedies the high mitotic index and rescues the premature differentiation of Mcph1 ‐deficient neuroprogenitors in vivo . MCPH1 itself is degraded by APC/C C dh1 , but not APC/C C dc20 , in late mitosis and G1 phase. Forced MCPH1 expression causes cell death, underlining the importance of MCPH1 turnover after mitosis. Ectopic expression of Cdh1 leads to premature differentiation of neuroprogenitors, mimicking differentiation defects of Mcph1 ‐knockout neuroprogenitors. The homeostasis of MCPH1 in association with the ubiquitin‐proteasome system ensures mitotic entry independent of cell cycle checkpoint. This study provides a mechanistic understanding of how MCPH1 controls neural stem cell fate and brain development. Synopsis Microcephalin (MCPH1) is mutated in the human neurodevelopmental disorder primary microcephaly type 1 (MCPH1), which is characterized by smaller‐than‐normal brain size. MCPH1 plays important roles in DNA damage response and cell cycle progression, which dictate proper neuroprogenitor fate. MCPH1 regulates βTrCP2‐mediated Cdc25A degradation in mitotic entry. MCPH1 is degraded by APC/C Cdh1 in late M and G1. The cell cycle‐dependent homeostasis of MCPH1 ensures proper neurogenesis. Graphical Abstract Neurogenesis is governed by microcephalin (MCPH1) degradation by APC/C Cdh1 and its regulation of βTrCP2‐mediated Cdc25A degradation during the cell cycle.