ESCRT-I protein UBAP1 controls ventricular expansion and cortical neurogenesis via modulating adherens junctions of radial glial cells

Intricate cerebral cortex formation is orchestrated by the precise behavior and division dynamics of radial glial cells (RGCs). Endocytosis functions in the recycling and remodeling of adherens junctions (AJs) in response to changes in RGC activity and function. Here, we show that conditional disruption of ubiquitin-associated protein 1 (UBAP1), a component of endosomal sorting complex required for transport (ESCRT), causes severe brain dysplasia and prenatal ventriculomegaly. UBAP1 depletion disrupts the AJs and polarity of RGCs, leading to failure of apically directed interkinetic nuclear migration. Accordingly, UBAP1 knockout or knockdown results in reduced proliferation and precocious differentiation of neural progenitor cells. Mechanistically, UBAP1 regulates the expression and surface localization of cell adhesion molecules, and β-catenin over-expression significantly rescues the phenotypes of Ubap1 knockdown in vivo. Our study reveals a critical physiological role of the ESCRT machinery in cortical neurogenesis by regulating AJs of RGCs. [Display omitted] •Loss of UBAP1 in neural stem cells causes progressive prenatal ventriculomegaly•UBAP1 modulates adherens junctions and polarity of radial glia cells•UBAP1 controls cortical neurogenesis in developing brain Lu et al. report that ESCRT component UBAP1 deficiency disrupts apical junctions and polarity of radial glia cells (RGCs), leading to cortical neurogenesis defects and prenatal ventriculomegaly, highlighting the importance of precisely regulating the adherens junctions of RGCs for cerebral ventricular expansion.