Usp11 controls cortical neurogenesis and neuronal migration through Sox11 stabilization.

Abstract

The role of protein stabilization in cortical development remains poorly understood. A recessive mutation in the <i>USP11</i> gene is found in a rare neurodevelopmental disorder with intellectual disability, but its pathogenicity and molecular mechanism are unknown. Here, we show that mouse <i>Usp11</i> is expressed highly in embryonic cerebral cortex, and <i>Usp11</i> deficiency impairs layer 6 neuron production, delays late-born neuronal migration, and disturbs cognition and anxiety behaviors. Mechanistically, these functions are mediated by a previously unidentified Usp11 substrate, Sox11. Usp11 ablation compromises Sox11 protein accumulation in the developing cortex, despite the induction of <i>Sox11</i> mRNA. The disease-associated Usp11 mutant fails to stabilize Sox11 and is unable to support cortical neurogenesis and neuronal migration. Our findings define a critical function of Usp11 in cortical development and highlight the importance of orchestrating protein stabilization mechanisms into transcription regulatory programs for a robust induction of cell fate determinants during early brain development.