Murine Jagged1/Notch signaling in the second heart field orchestrates Fgf8 expression and tissue-tissue interactions during outflow tract development
Murine Jagged1/Notch signaling in the second heart field orchestrates Fgf8 expression and tissue-tissue interactions during outflow tract development
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DOI：
10.1172/jci38922
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发表时间：
2009-07-01
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.;Jain, Rajan;Epstein, Jonathan A.
Notch信号对于人类和动物模型中心血管的正常发育和功能至关重要。事实上，JAGGED 或 NOTCH 突变会导致人类先天性心脏病，而 NOTCH 突变则与成人瓣膜病相关。 Notch 通常用于介导相邻组织之间的发育相互作用。在这里，我们表明，第二心脏区域组织中Notch配体Jagged1的缺失或Notch信号传导的抑制会导致小鼠主动脉弓动脉和心脏异常。在妊娠中期，这些突变体表现出 Fgf8 和 Bmp4 表达降低。第二心脏区域内的缺口抑制影响了邻近组织的发育。例如，观察到心脏神经嵴细胞的错误迁移和流出道心内膜垫内的内皮-间质转化缺陷。此外，在第二心区衍生物中Notch抑制后，外源性Fgfg足以挽救心内膜垫外植体测定中的内皮-间质转化缺陷。这些数据支持了一个将第二心脏区、神经嵴和心内膜垫发育联系起来的模型，并表明第二心脏区祖细胞内的Notch锯齿状信号传导受到干扰，可以解释某些形式的先天性和成人心脏病。
Notch signaling is vital for proper cardiovascular development and function in both humans and animal models. Indeed, mutations in either JAGGED or NOTCH cause congenital heart disease in humans and NOTCH mutations are associated with adult valvular disease. Notch typically functions to mediate developmental interactions between adjacent tissues. Here we show that either absence of the Notch ligand Jagged1 or inhibition of Notch signaling in second heart field tissues results in murine aortic arch artery and cardiac anomalies. In mid-gestation, these mutants displayed decreased Fgf8 and Bmp4 expression. Notch inhibition within the second heart field affected the development of neighboring tissues. For example, faulty migration of cardiac neural crest cells and defective endothelial-mesenchymal transition within the outflow tract endocardial cushions were observed. Furthermore, exogenous Fgfg was sufficient to rescue the defect in endothelial-mesenchymal transition in explant assays of endocardial cushions following Notch inhibition within second heart field derivatives. These data support a model that relates second heart field, neural crest, and endocardial cushion development and suggests that perturbed Notch-jagged signaling within second heart field progenitors accounts for some forms of congenital and adult cardiac disease.