Yap1 Is Required for Endothelial to Mesenchymal Transition of the Atrioventricular Cushion
Yap1 Is Required for Endothelial to Mesenchymal Transition of the Atrioventricular Cushion
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Yap1 是房室垫内皮细胞向间质细胞转变所必需的
DOI：
10.1074/jbc.m114.554584
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发表时间：
2014-07-11
影响因子：
4.8
通讯作者：
Zhou, Bin
中科院分区：
文献类型：
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作者：
Zhang, Hui;von Gise, Alexander;Zhou, Bin
由于房室（AV）瓣膜的异常发育导致的心脏畸形是先天性心脏病中最常见的形式。正常情况下，心脏瓣膜间充质是由内皮细胞垫的内皮细胞的内皮间充质转化（EMT）形成的。据报道，YAP 1除了作为脊椎动物器官大小和细胞增殖的主要调节因子外，还可在体外调节EMT，这使我们假设YAP 1是心脏瓣膜发育所必需的。我们通过内皮细胞及其衍生物中YAP 1的条件性失活来验证这一假设。由于EMT导致的心脏瓣膜间质形成受损和内皮细胞增殖减少，这导致了明显的低细胞内皮细胞垫。在内皮细胞中，TGF β诱导Smad 2/3/4复合物的核定位，其激活EMT所需的关键转录因子Snail、Twist 1和Slug的表达。YAP 1与这种复合物相互作用，YAP 1的缺失破坏了TGF β诱导的Snail，Twist 1和Slug的上调。总之，我们的研究结果确定了YAP 1在调节EMT中的作用，通过调节TGF β-Smad信号传导和通过心脏垫发育过程中的增殖活性。
Cardiac malformations due to aberrant development of the atrioventricular (AV) valves are among the most common forms of congenital heart diseases. Normally, heart valve mesenchyme is formed from an endothelial to mesenchymal transition (EMT) of endothelial cells of the endocardial cushions. Yes-associated protein 1 (YAP1) has been reported to regulate EMT in vitro, in addition to its known role as a major regulator of organ size and cell proliferation in vertebrates, leading us to hypothesize that YAP1 is required for heart valve development. We tested this hypothesis by conditional inactivation of YAP1 in endothelial cells and their derivatives. This resulted in markedly hypocellular endocardial cushions due to impaired formation of heart valve mesenchyme by EMT and to reduced endocardial cell proliferation. In endothelial cells, TGF beta induces nuclear localization of Smad2/3/4 complex, which activates expression of Snail, Twist1, and Slug, key transcription factors required for EMT. YAP1 interacts with this complex, and loss of YAP1 disrupts TGF beta-induced up-regulation of Snail, Twist1, and Slug. Together, our results identify a role of YAP1 in regulating EMT through modulation of TGF beta-Smad signaling and through proliferative activity during cardiac cushion development.