Cao Mou, Wu Jiang I
Department of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Neurosci Lett. 2015 Jun 15;597:71-6. doi: 10.1016/j.neulet.2015.04.041. Epub 2015 Apr 27.
Mammalian SWI/SNF-like BAF chromatin remodeling complexes are essential for many aspects of neural development. Mutations in the genes encoding the core subunit Brg1/SmarcA4 or other complex components cause neurodevelopmental diseases and are associated with autism. Congenital hydrocephalus is a serious brain disorder often experienced by these patients. We report a role of Brg1 in the pathogenesis of hydrocephalus disorder. We discovered an unexpected early activity of mouse Camk2a-Cre transgene, which mediates Brg1 deletion in a subset of forebrain neurons beginning in the late embryonic stage. Brg1 deletion in these neurons led to severe congenital hydrocephalus with enlargement of the lateral ventricles and attenuation of the cerebral cortex. The Brg1-deficient mice had significantly smaller subcommissural organs and narrower Sylvian aqueducts than mice that express normal levels of Brg1. Effects were non-cell autonomous and may be responsible for the development of the congenital hydrocephalus phenotype. Our study provides evidence indicating that abnormalities in Brg1 function result in defects associated with neurodevelopmental disorders and autism.
哺乳动物的SWI/SNF样BAF染色质重塑复合物对神经发育的许多方面至关重要。编码核心亚基Brg1/SmarcA4或其他复合物成分的基因突变会导致神经发育疾病，并与自闭症相关。先天性脑积水是这些患者常患的一种严重脑部疾病。我们报告了Brg1在脑积水疾病发病机制中的作用。我们发现了小鼠Camk2a-Cre转基因的一种意外的早期活性，它介导从胚胎后期开始在前脑神经元的一个子集中缺失Brg1。这些神经元中Brg1的缺失导致严重的先天性脑积水，伴有侧脑室扩大和大脑皮质变薄。与表达正常水平Brg1的小鼠相比，Brg1缺陷小鼠的连合下器官明显更小，大脑导水管更窄。这些影响是非细胞自主性的，可能是先天性脑积水表型发展的原因。我们的研究提供了证据，表明Brg1功能异常会导致与神经发育障碍和自闭症相关的缺陷。
