The role of protein stabilization in cortical development remains poorly understood. A recessive mutation in the gene is found in a rare neurodevelopmental disorder with intellectual disability, but its pathogenicity and molecular mechanism are unknown. Here, we show that mouse is expressed highly in embryonic cerebral cortex, and 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 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.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880594PMC
http://dx.doi.org/10.1126/sciadv.abc6093DOI Listing

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