The SWI/SNF BAF-A complex is essential for neural crest development.
The SWI/SNF BAF-A complex is essential for neural crest development.
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DOI：
10.1016/j.ydbio.2016.01.015
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发表时间：
2016-03-01
影响因子：
2.7
通讯作者：
Magnuson T
中科院分区：
文献类型：
--
作者：
Chandler RL;Magnuson T
越来越多的证据表明，染色质重塑突变是影响神经嵴细胞（NCC）的人类神经损伤或疾病的发病机制的基础。然而，染色质重塑亚基突变和NCC缺陷之间的因果关系仍然知之甚少。在这里，我们表明，纯合子丢失ARID 1A，SWI/SNF染色质重塑复合物（BAF-A）在NCC的结果在胚胎死亡的小鼠，与突变胚胎屈服于心脏缺陷。引人注目的是，NCC中ARID 1A的单等位基因缺失导致成年小鼠的颅面缺陷，包括缩短的鼻子和低耳，并且这些缺陷在ARID 1A纯合缺失后更加明显，腹侧颅骨的尺寸大大减小。在ARID 1A缺乏的情况下，早期NCC特异性和BRG 1 NCC靶基因PLEXINA 2的表达正常发生。尽管如此，突变胚胎显示心脏流出道圆锥动脉干分隔不完全和咽后动脉缺陷，最终导致动脉干持续存在和动脉导管发育不全。与此一致，迁移性心脏NCC在环咽嵴内发生凋亡。我们的数据支持多个不同的染色质重塑复合物在NCC发展中控制遗传上可分离的事件的观点，并强调了NCC在人类BAF复合物疾病Coffin-Siris综合征中的潜在致病作用。
Growing evidence indicates that chromatin remodeler mutations underlie the pathogenesis of human neurocristopathies or disorders that affect neural crest cells (NCCs). However, causal relationships among chromatin remodeler subunit mutations and NCC defects remain poorly understood. Here we show that homozygous loss of ARID1A-containing, SWI/SNF chromatin remodeling complexes (BAF-A) in NCCs results in embryonic lethality in mice, with mutant embryos succumbing to heart defects. Strikingly, monoallelic loss of ARID1A in NCCs led to craniofacial defects in adult mice, including shortened snouts and low set ears, and these defects were more pronounced following homozygous loss of ARID1A, with the ventral cranial bones being greatly reduced in size. Early NCC specification and expression of the BRG1 NCC target gene, PLEXINA2, occurred normally in the absence of ARID1A. Nonetheless, mutant embryos displayed incomplete conotruncal septation of the cardiac outflow tract and defects in the posterior pharyngeal arteries, culminating in persistent truncus arteriosus and agenesis of the ductus arteriosus. Consistent with this, migrating cardiac NCCs underwent apoptosis within the circumpharyngeal ridge. Our data support the notion that multiple, distinct chromatin remodeling complexes govern genetically separable events in NCC development and highlight a potential pathogenic role for NCCs in the human BAF complex disorder, Coffin-Siris Syndrome.