Myocardin-related transcription factor B is required in cardiac neural crest for smooth muscle differentiation and cardiovascular development
Myocardin-related transcription factor B is required in cardiac neural crest for smooth muscle differentiation and cardiovascular development
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DOI：
10.1073/pnas.0503741102
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发表时间：
2005-06-21
影响因子：
11.1
通讯作者：
Parmacek, MS
中科院分区：
文献类型：
--
作者：
Li, J;Zhu, XH;Parmacek, MS
肌心蛋白相关转录因子家族的成员在调节血管平滑肌和心脏分化中起关键作用。为了检测肌心蛋白相关转录因子（MRTF）-B的功能，从携带MRTF-B基因的条件性插入突变或基因陷阱的ES细胞产生小鼠。MRTF-B突变等位基因的表达导致由MRTF-B的N末端融合至β-半乳糖苷酶组成的融合蛋白，其功能无效。纯合子MRTF-B基因诱捕小鼠（MRTF-B-/-）在胚胎第17.5天至出生后第1天死于心脏流出道缺陷。MRTF-B表达于迁移前神经嵴、第3和第5菱节以及主动脉弓动脉周围的神经嵴衍生间充质。与表达模式一致，E10.5和E11.5 MRTF-B-/-突变体显示主动脉弓动脉3、4和6的变形，以及主动脉弓动脉和主动脉弓间隔中平滑肌细胞分化的严重衰减，尽管心脏神经嵴细胞的正常迁移和初始模式。值得注意的是，所观察到的病理被挽救，并且通过将MRTF-B突变体与在神经嵴限制性Wnt-1启动子的转录控制下表达Cre重组酶的小鼠杂交产生存活的小鼠，这导致神经嵴中正常MRTF-B表达的恢复。总之，这些研究表明，MRTF-B在调节心脏神经嵴细胞分化成平滑肌中起着关键作用，并证明神经嵴衍生的平滑肌分化是正常心血管形态发生所特别需要的。
Members of the myocardin-related family of transcription factors play critical roles in regulating vascular smooth muscle and cardiac differentiation. To examine the function of myocardin-related transcription factor (MRTF)-B, mice were generated from ES cells harboring a conditional insertional mutation, or gene trap, of the MRTF-B gene. Expression of the MRTF-B mutant allele results in a fusion protein consisting of the N terminus of MRTF-B fused to p-galactosidase, which is functionally null. Homozygous MRTF-B gene trap mice (MRTF-B-/-) die between embryonic day (E)17.5 and postnatal day 1 from cardiac outflow tract defects. MRTF-B is expressed in the premigratory neural crest, in rhombomeres 3 and 5, and in the neural crest-derived mesenchyme surrounding the aortic arch arteries. Consistent with the pattern of expression, E10.5 and E11.5 MRTF-B-/- mutants exhibit deformation of aortic arch arteries 3, 4, and 6 and severe attenuation of smooth muscle cell differentiation in the arch arteries and the aorticopulmonary septum, despite normal migration and initial patterning of cardiac neural crest cells. Remarkably, the observed pathology was rescued and viable mice generated by intercrossing MRTF-B mutants with mice expressing Cre recombinase under the transcriptional control of the neural crest-restricted Wnt-1 promoter, which results in restoration of normal MRTF-B expression in the neural crest. Taken together, these studies reveal that MRTF-B plays a critical role in regulating differentiation of cardiac neural crest cells into smooth muscle and demonstrate that neural crest-derived smooth muscle differentiation is specifically required for normal cardiovascular morphogenesis.