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 USP11 gene is found in a rare neurodevelopmental disorder with intellectual disability, but its pathogenicity and molecular mechanism are unknown. Here, we show that mouse Usp11 is expressed highly in embryonic cerebral cortex, and Usp11 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 Sox11 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.

Mitotic WNT signalling orchestrates neurogenesis in the developing neocortex

“…Consistent with this possibility, phosphorylation by GSK3β induced ubiquitination and decreased overall Sox4 and Sox11 levels. Previous reports have shown that, in the neocortex, Sox11 cellular localization and protein stabilization are regulated by phosphorylation and ubiquitination, respectively, supporting that post‐transcriptional regulation of Sox11 is essential for its function in vivo (Balta et al , 2018a ; Balta et al , 2018b ; Chiang et al , 2021 ).…”

Neural stemness unifies cell tumorigenicity and pluripotent differentiation potential

“…SETDB1 also interacted with the proteasome component proteins PSMD2 and ADRM1, and USP11 (Fig. 5A), a deubiquitinase that is expressed primarily in the embryonic nervous system, regulates neurogenesis and neuronal migration and, accordingly, is upregulated in cancer cells and promotes cancer (31)(32)(33).…”

Long noncoding RNA BCRP3 stimulates VPS34 and autophagy activities to promote protein homeostasis and cell survival

“…NanoLC−nanoESi-MS/MS analysis was performed on a Thermo UltiMate 3000 RSLCnano system connected to a Thermo Orbitrap Fusion mass spectrometer (Thermo Fisher Scientific, Bremen, Germany) equipped with a nanospray interface (New Objective, Woburn, MA, USA) and followed procedures as described previously [ 28 ]. Peptide mixtures were loaded onto a 75 μm ID, 25 cm length PepMap C18 column (Thermo Fisher Scientific) packed with 2 μm particles with a pore width of 100 Å and were separated using a segmented gradient in 120 min from 5 to 35% solvent B (0.1% formic acid in acetonitrile) at a flow rate of 300 nl/min.…”