Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 100, Taiwan.
Sci Adv. 2021 Feb 12;7(7). doi: 10.1126/sciadv.abc6093. Print 2021 Feb.
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.
蛋白质稳定化在皮质发育中的作用仍知之甚少。一种罕见的神经发育障碍伴智力残疾的患者中发现了基因的隐性突变，但尚不清楚其致病性和分子机制。在这里，我们表明，小鼠在胚胎大脑皮质中高度表达，并且缺失会损害 6 层神经元的产生，延迟晚期出生的神经元迁移，并扰乱认知和焦虑行为。在机制上，这些功能是由以前未被识别的 Usp11 底物 Sox11 介导的。Usp11 缺失会破坏发育中的皮质中 Sox11 蛋白的积累，尽管诱导了 mRNA。与疾病相关的 Usp11 突变体不能稳定 Sox11，也不能支持皮质神经发生和神经元迁移。我们的发现定义了 Usp11 在皮质发育中的关键功能，并强调了协调蛋白质稳定机制到转录调控程序中的重要性，以在早期大脑发育中稳健诱导细胞命运决定因素。
