Loss of BAF (mSWI/SNF) chromatin-remodeling ATPase Brg1 causes multiple malformations of cortical development in mice
Loss of BAF (mSWI/SNF) chromatin-remodeling ATPase Brg1 causes multiple malformations of cortical development in mice
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BAF (mSWI/SNF) 染色质重塑 ATP 酶 Brg1 的缺失导致小鼠皮质发育的多种畸形
DOI：
10.1093/hmg/ddac127
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发表时间：
2022
影响因子：
3.5
通讯作者：
Jiangang Gao
中科院分区：
文献类型：
--
作者：
Yecheng Jin;Xiaotong Gao;Miaoqing Lu;Ge Chen;Xiaofan Yang;Naixia Ren;Yuning Song;Congzhe Hou;Jiangxia Li;Qiji Liu;Jiangang Gao
摘要编码BRG1/BRM相关因子(BRG1/BRM)复合体亚单位的基因突变可导致多种神经发育疾病。然而，其潜在的病理生理学在很大程度上仍不清楚。在这里，我们分析了BAF复合体的核心ATPase BRG1在大脑皮层发育中的功能。BRG1的缺失会导致一些类似人类皮质发育畸形(MCDS)的形态缺陷，包括小头畸形、皮质发育不良、鹅卵石般的无脑和脑室周围异位。我们发现BRG1缺失后，与MCD形成相关的神经前体细胞(NPC)更新、神经元分化、神经元迁移、凋亡细胞死亡、软膜基底膜和顶端连接复合体受到损害。此外，转录组图谱显示，大量基因被解除调控。这些非调控基因与MCD的形成密切相关，并且大多数基因都与BRG1结合。总体而言，我们的研究表明BRG1在皮质发育中起着重要作用，并为基于BRG1的BAF复合体相关神经发育障碍提供了一种新的可能的发病机制。
Abstract Mutations in genes encoding subunits of the BAF (BRG1/BRM-associated factor) complex cause various neurodevelopmental diseases. However, the underlying pathophysiology remains largely unknown. Here, we analyzed the function of Brg1, a core ATPase of BAF complexes, in the developing cerebral cortex. Loss of Brg1 causes several morphological defects resembling human malformations of cortical development (MCDs), including microcephaly, cortical dysplasia, cobblestone lissencephaly, and periventricular heterotopia. We demonstrated that neural progenitor cell (NPC) renewal, neuronal differentiation, neuronal migration, apoptotic cell death, pial basement membrane, and apical junctional complexes, which are associated with MCD formation, were impaired after Brg1 deletion. Furthermore, transcriptome profiling indicated that a large number of genes were deregulated. The deregulated genes were closely related to MCD formation, and most of these genes were bound by Brg1. Cumulatively, our study indicates an essential role of Brg1 in cortical development and provides a new possible pathogenesis underlying Brg1-based BAF complex-related neurodevelopmental disorders.