Holdhof Dörthe, Schoof Melanie, Al-Kershi Sina, Spohn Michael, Kresbach Catena, Göbel Carolin, Hellwig Malte, Indenbirken Daniela, Moreno Natalia, Kerl Kornelius, Schüller Ulrich
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Research Institute Children's Cancer Center Hamburg, 20251 Hamburg, Germany.
Development. 2021 May 15;148(10). doi: 10.1242/dev.196147. Epub 2021 May 27.
During development, gene expression is tightly controlled to facilitate the generation of the diverse cell types that form the central nervous system. Brahma-related gene 1 (Brg1, also known as Smarca4) is the catalytic subunit of the SWItch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex that regulates transcription. We investigated the role of Brg1 between embryonic day 6.5 (E6.5) and E14.5 in Sox2-positive neural stem cells (NSCs). Being without major consequences at E6.5 and E14.5, loss of Brg1 between E7.5 and E12.5 resulted in the formation of rosette-like structures in the subventricular zone, as well as morphological alterations and enlargement of neural retina (NR). Additionally, Brg1-deficient cells showed decreased survival in vitro and in vivo. Furthermore, we uncovered distinct changes in gene expression upon Brg1 loss, pointing towards impaired neuron functions, especially those involving synaptic communication and altered composition of the extracellular matrix. Comparison with mice deficient for integrase interactor 1 (Ini1, also known as Smarcb1) revealed that the enlarged NR was Brg1 specific and was not caused by a general dysfunction of the SWI/SNF complex. These results suggest a crucial role for Brg1 in NSCs during brain and eye development.
在发育过程中，基因表达受到严格控制，以促进形成中枢神经系统的多种细胞类型的产生。与婆罗门相关的基因1（Brg1，也称为Smarca4）是调节转录的SWItch/蔗糖非发酵（SWI/SNF）染色质重塑复合体的催化亚基。我们研究了Brg1在胚胎第6.5天（E6.5）至E14.5期间在Sox2阳性神经干细胞（NSCs）中的作用。在E6.5和E14.5时没有重大影响，但在E7.5至E12.5期间Brg1的缺失导致脑室下区形成玫瑰花结样结构，以及神经视网膜（NR）的形态改变和增大。此外，Brg1缺陷细胞在体外和体内均显示存活率降低。此外，我们发现Brg1缺失后基因表达有明显变化，表明神经元功能受损，尤其是那些涉及突触通讯和细胞外基质组成改变的功能。与整合酶相互作用因子1（Ini1，也称为Smarcb1）缺陷的小鼠比较发现，NR增大是Brg1特有的，并非由SWI/SNF复合体的一般功能障碍引起。这些结果表明Brg1在脑和眼发育过程中的神经干细胞中起关键作用。
