Abstract

Neural progenitor cell (NPC) proliferation is fundamental for population expansion and brain development. G1 phase control determines the cell cycle duration of NPCs and thereby affects their proliferation efficiency. However, the molecular mechanisms governing G1 phase progression in NPCs remain unclear. Here, we show that AKT gain-of-function mutations and pharmacological inhibition exert opposing effects on NPC proliferation. Consistently, Emx1-Cre-mediated deletion of Akt1/2/3 in mice impairs NPC proliferation and disrupts cortical development. We find that AKT deficiency induces G1 phase arrest and prolongs the cell cycle of NPCs. Mechanistically, we demonstrate that AKT-mediated phosphorylation inhibits the activity of CRL4AMBRA1 E3 ubiquitin ligase to safeguard cyclin D2 (CCND2) stability. Specifically, AKT phosphorylates DDB1, the adaptor of CRL4AMBRA1, which disrupts its interaction with CCND2 and reduces its degradation. These findings reveal a post-translational mechanism impacting NPC cell cycle and cortical morphogenesis, providing insight into the etiology of malformations of cortical development. This study reveals a post-translational mechanism impacting NPC cell cycle and cortical morphogenesis, showing that AKT maintains CCND2 stability through inhibition of CRL4AMBRA1 activity during NPC G1 phase progression. Genetic deletion of Akt1/2/3 in mice impairs NPC proliferation and disrupts cortical development. AKT deficiency induces G1 phase arrest and prolongs the cell cycle of NPCs. AKT phosphorylates DDB1, the adaptor of CRL4AMBRA1, to reduce CCND2 degradation. Genetic deletion of Akt1/2/3 in mice impairs NPC proliferation and disrupts cortical development. AKT deficiency induces G1 phase arrest and prolongs the cell cycle of NPCs. AKT phosphorylates DDB1, the adaptor of CRL4AMBRA1, to reduce CCND2 degradation.