Chromatin regulation by BAF complex controls cortical astrogenesis

星形胶质细胞是人脑中最大的细胞群，对大脑发育至关重要。星形发育缺陷与神经疾病有关，如Rett综合征、脆性X综合征和脑肿瘤。因此，了解星形胶质细胞是如何生成的非常重要。染色质重塑SWI/SNF(Switch/Sucose non Fermentable)复合体，也被称为BAF(BRG1/BRM Association Function)复合体，在脑发育中起着至关重要的作用，然而，它在星形胶质细胞发生中的作用却鲜为人知。我们的表达分析表明，BAF155和BAF170两个Paralog亚基在所有已知的小鼠皮质星形胶质细胞来源中都有表达，例如脑室区(VZ)的晚期皮质前体细胞(E17.5-E18.5)，室下区(SVZ)和齿状回(DG)的成年神经干细胞(ANSCs)，以及幼年小鼠皮质层的分裂星形胶质细胞(也称为星形胶质细胞前体)。此外，我们的初步蛋白质组学数据表明，这两个BAF亚基在体内都与关键因子相互作用，这些因子在星形发育中起着关键作用。本研究的主要目的是描述BAF155和BAF170突变小鼠的星形胶质细胞表型。其次，我们的目标是通过结合基因组、蛋白质组、先进的成像和遗传操作技术来研究依赖于BAF155和BAF170的机制，这些机制控制着星形细胞的发育。这项研究将为研究mSWI/SNF染色质重塑复合体控制星形形成的分子机制提供有价值的见解。

“Astrocytes constitute the largest cell population in the human brain and are crucial for the brain development. Defects in astrogenesis are linked with neurological disorders such as Rett syndrome, fragile X syndrome, and brain tumors. Therefore, it is important to understand how astrocytes are generated.The chromatin remodeling SWI/SNF (SWItch/Sucrose NonFermentable) complex, also known as BAF (Brg1/Brm Associated Factors) complex, plays an essential role in brain development, however, its function in astrogenesis is largely unknown. Our expression analysis indicated that two paralog subunits BAF155 and BAF170 are expressed in all known murine cortical astrocyte sources such as late cortical progenitors (E17.5-E18.5) of the ventricular zone (VZ), adult neural stem cells (aNSCs) in the subventricular zone (SVZ) and dentate gyrus (DG), and dividing astrocytes (also known as astrocyte precursors) in the cortical layers of juvenile mice. In addition, our preliminary proteomic data indicates that the both BAF subunit interacts in vivo with key factors, which were known to play a key role in astrogenesis.The primary aim of this proposal is to characterize the astrocytic phenotypes of BAF155 and BAF170 mutant mice. Secondly, we aim to study the BAF155 and BAF170-dependent mechanisms that control astrocytic development by applying a combination of genomic, proteomic approaches, advanced imaging and genetic manipulation techniques. This study would provide valuable insights into the molecular mechanism, which is mediated by the mSWI/SNF chromatin remodeling complex that controls astrogenesis”.