School of Biomedical Sciences, The University of Queensland, Brisbane 4072, Australia.
Griffith Institute for Drug Discovery, Griffith University, Brisbane 4111, Australia.
Cereb Cortex. 2021 Feb 5;31(3):1763-1775. doi: 10.1093/cercor/bhaa324.
Genetic association studies have identified many factors associated with neurodevelopmental disorders such as autism spectrum disorder (ASD). However, the way these genes shape neuroanatomical structure and connectivity is poorly understood. Recent research has focused on proteins that act as points of convergence for multiple factors, as these may provide greater insight into understanding the biology of neurodevelopmental disorders. USP9X, a deubiquitylating enzyme that regulates the stability of many ASD-related proteins, is one such point of convergence. Loss of function variants in human USP9X lead to brain malformations, which manifest as a neurodevelopmental syndrome that frequently includes ASD, but the underlying structural and connectomic abnormalities giving rise to patient symptoms is unknown. Here, we analyzed forebrain-specific Usp9x knockout mice (Usp9x-/y) to address this knowledge gap. Usp9x-/y mice displayed abnormal communication and social interaction behaviors. Moreover, the absence of Usp9x culminated in reductions to the size of multiple brain regions. Diffusion tensor magnetic resonance imaging revealed deficits in all three major forebrain commissures, as well as long-range hypoconnectivity between cortical and subcortical regions. These data identify USP9X as a key regulator of brain formation and function, and provide insights into the neurodevelopmental syndrome arising as a consequence of USP9X mutations in patients.
遗传关联研究已经确定了许多与神经发育障碍相关的因素，例如自闭症谱系障碍（ASD）。然而，这些基因塑造神经解剖结构和连接的方式还知之甚少。最近的研究集中在作为多种因素汇聚点的蛋白质上，因为这些蛋白质可能更深入地了解神经发育障碍的生物学。USP9X 是一种去泛素化酶，可调节许多与 ASD 相关的蛋白质的稳定性，是这样的汇聚点之一。人类 USP9X 中的功能丧失变异会导致脑畸形，表现为神经发育综合征，通常包括 ASD，但导致患者症状的潜在结构和连接异常尚不清楚。在这里，我们分析了大脑特异性 Usp9x 敲除小鼠（Usp9x-/y）以解决这一知识空白。Usp9x-/y 小鼠表现出异常的交流和社交互动行为。此外，Usp9x 的缺失导致多个大脑区域的大小减小。弥散张量磁共振成像显示，所有三个主要的大脑前连合都存在缺陷，以及皮质和皮质下区域之间的长程低连接。这些数据表明 USP9X 是大脑形成和功能的关键调节剂，并为患者 USP9X 突变引起的神经发育综合征提供了深入了解。
