Chromatin regulation by BAF170 controls cerebral cortical size and thickness

Increased cortical size is essential to the enhanced intellectual capacity of primates during mammalian evolution. The mechanisms that control cortical size are largely unknown. Here, we show that mammalian BAF170, a subunit of the chromatin remodeling complex mSWI/SNF, is an intrinsic factor that controls cortical size. We find that the conditional deletion of BAF170 promotes indirect neurogenesis by increasing the pool of intermediate progenitors (IPs) and results in an enlarged cortex, whereas cortex-specific BAF170 over-expression results an opposing phenotype. Mechanistically, BAF170 competes with BAF155 subunit in the BAF complex, affecting the euchromatin structure and thereby modulating the binding efficiency of Pax6/REST-corepressor complex to Pax6 target genes that regulate the generation of IPs and late cortical progenitors. Our findings reveal a molecular mechanism mediated by the mSWI/SNF chromatin-remodeling complex that controls cortical architecture. Cortical gene expression is compared between three E12.5 mouse embryos with cortex-specific loss of BAF170 function and three littermate control embryos.在哺乳动物演化历程中，皮层体积增大是灵长类动物智力提升的核心基础。目前学界对调控皮层体积的分子机制尚未完全阐明。本研究证实，哺乳动物BAF170——染色质重塑复合物mSWI/SNF的一个亚基——是调控皮层体积的内在因子。我们发现，条件性敲除BAF170可通过扩大中间前体细胞（IPs）库促进间接神经发生，最终导致皮层体积增大；而皮层特异性过表达BAF170则会产生相反的表型。从机制层面来看，BAF170可在BAF复合物中与BAF155亚基竞争结合位点，进而改变常染色质结构，调控Pax6/REST共阻遏复合物与Pax6靶基因的结合效率——这些靶基因参与调控中间前体细胞的生成以及晚期皮层前体细胞的产生。本研究揭示了一条由mSWI/SNF染色质重塑复合物介导的、调控皮层发育架构的分子机制。本研究对3例皮层特异性BAF170功能缺失的胚胎发育第12.5天（E12.5）小鼠胚胎，与3例同窝对照胚胎的皮层基因表达谱开展了对比分析。