Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA.
Department of Developmental Biology, Stanford University, California 94305, USA.
Genes Dev. 2021 Mar 1;35(5-6):335-353. doi: 10.1101/gad.342345.120. Epub 2021 Feb 18.
mSWI/SNF or BAF chromatin regulatory complexes are dosage-sensitive regulators of human neural development frequently mutated in autism spectrum disorders and intellectual disability. Cell cycle exit and differentiation of neural stem/progenitor cells is accompanied by BAF subunit switching to generate neuron-specific nBAF complexes. We manipulated the timing of BAF subunit exchange in vivo and found that early loss of the npBAF subunit BAF53a stalls the cell cycle to disrupt neurogenesis. Loss of BAF53a results in decreased chromatin accessibility at specific neural transcription factor binding sites, including the pioneer factors SOX2 and ASCL1, due to Polycomb accumulation. This results in repression of cell cycle genes, thereby blocking cell cycle progression and differentiation. Cell cycle block upon deletion could be rescued by premature expression of the nBAF subunit BAF53b but not by other major drivers of proliferation or differentiation. WNT, EGF, bFGF, SOX2, c-MYC, or PAX6 all fail to maintain proliferation in the absence of BAF53a, highlighting a novel mechanism underlying neural progenitor cell cycle exit in the continued presence of extrinsic proliferative cues.
mSWI/SNF 或 BAF 染色质调控复合物是人类神经发育的剂量敏感调节剂，常发生在自闭症谱系障碍和智力障碍中。神经干细胞/祖细胞的细胞周期退出和分化伴随着 BAF 亚基的转换，以产生神经元特异性 nBAF 复合物。我们在体内操纵 BAF 亚基交换的时间，发现 npBAF 亚基 BAF53a 的早期缺失会使细胞周期停滞，从而破坏神经发生。BAF53a 的缺失导致特定神经转录因子结合位点的染色质可及性降低，包括先驱因子 SOX2 和 ASCL1，这是由于多梳蛋白的积累。这导致细胞周期基因的抑制，从而阻止细胞周期的进展和分化。在删除时，细胞周期的阻断可以通过过早表达 nBAF 亚基 BAF53b 来挽救，但不能通过其他主要的增殖或分化驱动因素来挽救。WNT、EGF、bFGF、SOX2、c-MYC 或 PAX6 都不能在没有 BAF53a 的情况下维持增殖，这突出了神经祖细胞在持续存在外在增殖信号的情况下退出细胞周期的一种新机制。
