An essential role for Notch in neural crest during cardiovascular development and smooth muscle differentiation
An essential role for Notch in neural crest during cardiovascular development and smooth muscle differentiation
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DOI：
10.1172/jci30070
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发表时间：
2007-02-01
影响因子：
15.9
通讯作者：
Epstein, Jonathan A.
中科院分区：
文献类型：
--
作者：
High, Frances A.;Zhang, Maozhen;Epstein, Jonathan A.
心脏流出道的发育是几种细胞类型之间复杂相互作用的结果，包括心脏神经嵴细胞、内皮细胞和心肌细胞。在人类和小鼠中，Notch信号通路组分的突变导致以心脏流出道缺陷为特征的先天性心脏病。然而，Notch在心血管发育过程中发挥作用的特定细胞类型仍有待确定。此外，体外研究提供了关于Notch促进或抑制平滑肌分化的能力的相互矛盾的数据，而Notch在发育期间平滑肌形成中的生理作用仍不清楚。在这项研究中，我们产生了小鼠，其中Notch信号在神经嵴的衍生物中特异性失活。这些小鼠表现出心血管异常，包括主动脉弓图案缺陷、肺动脉狭窄和室间隔缺损。我们表明，Notch在体外和体内心脏神经嵴前体分化为平滑肌细胞中起着关键的细胞自主作用，我们确定了参与这一过程的神经嵴中的特定Notch靶点。这些结果为理解Notch信号在先天性心脏病病因学中的作用提供了分子和细胞框架。
The cardiac outflow tract develops as a result of a complex interplay among several cell types, including cardiac neural crest cells, endothelial cells, and cardiomyocytes. In both humans and mice, mutations in components of the Notch signaling pathway result in congenital heart disease characterized by cardiac outflow tract defects. However, the specific cell types in which Notch functions during cardiovascular development remain to be defined. In addition, in vitro studies have provided conflicting data regarding the ability of Notch to promote or inhibit smooth muscle differentiation, while the physiological role for Notch in smooth muscle formation during development remains unclear. in this study, we generated mice in which Notch signaling was specifically inactivated in derivatives of the neural crest. These mice exhibited cardiovascular anomalies, including aortic arch patterning defects, pulmonary artery stenosis, and ventricular septal defects. We show that Notch plays a critical, cell-autonomous role in the differentiation of cardiac neural crest precursors into smooth muscle cells both in vitro and in vivo, and we identify specific Notch targets in neural crest that are implicated in this process. These results provide a molecular and cellular framework for understanding the role of Notch signaling in the etiology of congenital heart disease.