Ets1 is required for proper migration and differentiation of the cardiac neural crest
Ets1 is required for proper migration and differentiation of the cardiac neural crest
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DOI：
10.1242/dev.047696
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发表时间：
2010-05-01
期刊：
影响因子：
4.6
通讯作者：
Svensson, Eric C.
中科院分区：
文献类型：
--
作者：
Gao, Zhiguang;Kim, Gene H.;Svensson, Eric C.
心脏神经嵴缺损可导致心脏流出道衰竭和心室间隔缺损，从而导致先天性心脏病。在这份报告中，我们证明了一个以前不受重视的作用，转录因子Ets 1在心脏神经嵴发育的调节。当在C57 BL/6遗传背景下繁殖时，Ets 1-/-小鼠具有几乎完全的围产期致死性。对Ets 1（-/-）胚胎的组织学检查显示，心脏内存在膜性室间隔缺损和异常软骨结节。在Ets 1（-/-）小鼠中的谱系追踪实验表明，神经嵴谱系的细胞形成这种软骨结节，并且没有完成它们向流出道内膜垫的近端方面的迁移，导致膜性室间隔形成失败。鉴于先前的研究表明MEK/ERK途径直接调节Ets 1活性，我们在MEK抑制剂U 0126存在下培养胚胎心脏，发现U 0126诱导心内软骨形成，表明MEK/ERK/Ets 1途径参与阻断心脏神经嵴的软骨细胞分化。综上所述，这些结果表明，Ets 1是需要指导适当的迁移和分化的心脏神经嵴的室间隔的形成，因此可以发挥作用，在人类先天性心脏病的病因。
Defects in cardiac neural crest lead to congenital heart disease through failure of cardiac outflow tract and ventricular septation. In this report, we demonstrate a previously unappreciated role for the transcription factor Ets1 in the regulation of cardiac neural crest development. When bred onto a C57BL/6 genetic background, Ets1 -/-mice have a nearly complete perinatal lethality. Histologic examination of Ets1(-/-) embryos revealed a membranous ventricular septal defect and an abnormal nodule of cartilage within the heart. Lineage-tracing experiments in Ets1(-/-) mice demonstrated that cells of the neural crest lineage form this cartilage nodule and do not complete their migration to the proximal aspects of the outflow tract endocardial cushions, resulting in the failure of membranous interventricular septum formation. Given previous studies demonstrating that the MEK/ERK pathway directly regulates Ets1 activity, we cultured embryonic hearts in the presence of the MEK inhibitor U0126 and found that U0126 induced intra-cardiac cartilage formation, suggesting the involvement of a MEK/ERK/Ets1 pathway in blocking chondrocyte differentiation of cardiac neural crest. Taken together, these results demonstrate that Ets1 is required to direct the proper migration and differentiation of cardiac neural crest in the formation of the interventricular septum, and therefore could play a role in the etiology of human congenital heart disease.