CRL4^AMBRA1 is a key mediator for AKT-dependent cell cycle control in neural progenitor cells

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 CRL4^AMBRA1 E3 ubiquitin ligase to safeguard cyclin D2 (CCND2) stability. Specifically, AKT phosphorylates DDB1, the adaptor of CRL4^AMBRA1, 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.