Brg1 governs distinct pathways to direct multiple aspects of mammalian neural crest cell development
Brg1 governs distinct pathways to direct multiple aspects of mammalian neural crest cell development
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DOI：
10.1073/pnas.1218072110
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发表时间：
2013-01-29
影响因子：
11.1
通讯作者：
Chang, Ching-Pin
中科院分区：
文献类型：
--
作者：
Li, Wei;Xiong, Yiqin;Chang, Ching-Pin
脑血管、咽弓动脉（PAA）的发育。心脏流出道（OFT）需要从神经管迁移到靶组织目的地的多能神经嵴细胞（NCC）。然而，关于哺乳动物NCC的发育是如何在染色质水平上通过基因编程来协调的，我们知之甚少。在这里，我们表明，梵天相关基因1（Brg 1），一个ATP酶亚基的Brg 1/梵天相关因子（BAF）染色质重塑复合物，是需要在NCC直接心血管发展。在NCC中缺乏Brg 1的小鼠胚胎显示不成熟的脑血管，异常的PAA模式和缩短的OFT。Brg 1抑制凋亡因子凋亡信号调节激酶1（Ask 1）和细胞周期抑制剂p21（cip 1），以抑制细胞凋亡并促进NCC增殖，从而维持神经嵴处的多能细胞库。Brg 1还支持肌球蛋白重链11（Myh 11）的表达，使NCC发育成成熟的脑血管平滑肌细胞。在NCC内，Brg 1与丛蛋白A2启动子上的染色质重塑剂Chromodomain-helicase-DNA结合蛋白7（Chd 7）合作以激活丛蛋白A2，丛蛋白A2编码脑信号蛋白的受体以引导NCC进入OFT。我们的研究结果揭示了Brg 1及其下游通路在哺乳动物心血管发育关键的多能NCC的生存，分化和迁移中的重要作用。
Development of the cerebral vessels, pharyngeal arch arteries (PAAs). and cardiac outflow tract (OFT) requires multipotent neural crest cells (NCCs) that migrate from the neural tube to target tissue destinations. Little is known about how mammalian NCC development is orchestrated by gene programming at the chromatin level, however. Here we show that Brahma-related gene 1 (Brg1), an ATPase subunit of the Brg1/Brahma-associated factor (BAF) chromatin-remodeling complex, is required in NCCs to direct cardiovascular development. Mouse embryos lacking Brg1 in NCCs display immature cerebral vessels, aberrant PAA patterning, and shortened OFT. Brg1 suppresses an apoptosis factor, Apoptosis signal-regulating kinase 1 (Ask1), and a cell cycle inhibitor, p21(cip1), to inhibit apoptosis and promote proliferation of NCCs, thereby maintaining a multipotent cell reservoir at the neural crest. Brg1 also supports Myosin heavy chain 11 (Myh11) expression to allow NCCs to develop into mature vascular smooth muscle cells of cerebral vessels. Within NCCs, Brg1 partners with chromatin remodeler Chromodomain-helicase-DNA-binding protein 7 (Chd7) on the PlexinA2 promoter to activate PlexinA2, which encodes a receptor for semaphorin to guide NCCs into the OFT. Our findings reveal an important role for Brg1 and its downstream pathways in the survival, differentiation, and migration of the multipotent NCCs critical for mammalian cardiovascular development.