Loss of BAF (mSWI/SNF) chromatin-remodeling ATPase Brg1 causes multiple malformations of cortical development in mice

• Published in: Human molecular genetics 2022-10, Vol.31 (20), p.3504-3520
• Main Authors: Jin, Yecheng, Gao, Xiaotong, Lu, Miaoqing, Chen, Ge, Yang, Xiaofan, Ren, Naixia, Song, Yuning, Hou, Congzhe, Li, Jiangxia, Liu, Qiji, Gao, Jiangang
• Format: Article
• Language: English
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddac127

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.