MEKK3 initiates transforming growth factor beta 2-dependent epithelial-to-mesenchymal transition during endocardial cushion morphogenesis.
MEKK3 initiates transforming growth factor beta 2-dependent epithelial-to-mesenchymal transition during endocardial cushion morphogenesis.
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MEKK3启动了内膜垫形态发生过程中转化生长因子β2依赖性上皮到间质转变。
DOI：
10.1161/circresaha.108.180752
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发表时间：
2008-12-05
影响因子：
20.1
通讯作者：
Camenisch TD
中科院分区：
文献类型：
--
作者：
Stevens MV;Broka DM;Parker P;Rogowitz E;Vaillancourt RR;Camenisch TD
先天性心脏缺陷（CHD）的发生率为5%，是最常见的出生缺陷。更好地了解调节心脏发育的复杂信号网络对于改善CHD的修复策略是必要的。MAP 3激酶MEKK 3对早期胚胎发生很重要，但在心脏形态发生过程中受MEKK 3影响的发育过程尚未得到充分研究。我们确定MEKK 3作为一个关键的信号分子在内膜垫的发展。我们报告检测MEKK 3转录胚胎心脏之前，期间和之后的心脏垫细胞已执行上皮间充质转化（EMT）。观察到MEKK 3以递减的表达梯度进入心脏垫的内皮细胞。这些观察结果表明，MEKK 3可能在产生心脏瓣膜发育和分隔所需的垫间充质期间起作用。我们在体外试验中使用了激酶失活形式的MEKK 3（MEKK 3 KI），其重现了体内EMT，并显示MEKK 3 KI减弱间充质形成。相反，组成型活性MEKK 3（ca-MEKK 3）触发心室内膜中的间充质产生，心室内膜是通常不经历EMT的组织。MEKK 3驱动的间充质产生进一步通过EMT相关基因（包括TGFβ2、Has 2和骨膜蛋白）的表达增加得到证实。此外，我们发现MEKK 3通过TGFβ2依赖性机制刺激EMT。因此，MEKK 3的活性足以在心脏中发育EMT。这些知识为理解MEKK 3如何整合激活内皮细胞垫EMT的信号级联提供了基础。
Congenital heart defects (CHDs) occur at a rate of five percent and are the most prevalent birth defects. A better understanding of the complex signaling networks regulating heart development is necessary to improve repair strategies for CHDs. The MAP3 kinase, MEKK3, is important to early embryogenesis, but developmental processes affected by MEKK3 during heart morphogenesis have not been fully examined. We identify MEKK3 as a critical signaling molecule during endocardial cushion development. We report the detection of MEKK3 transcripts to embryonic hearts prior, during and after cardiac cushion cells have executed epithelial to mesenchymal transformation (EMT). MEKK3 is observed to endocardial cells of the cardiac cushions with a diminishing gradient of expression into the cushions. These observations suggest that MEKK3 may function during production of cushion mesenchyme as required for valvular development and septation of the heart. We used a kinase inactive form of MEKK3 (MEKK3KI) in an in vitro assay that recapitulates in vivo EMT, and show that MEKK3KI attenuates mesenchyme formation. Conversely, constitutively active MEKK3 (ca-MEKK3) triggers mesenchyme production in ventricular endocardium, a tissue that does not normally undergo EMT. MEKK3-driven mesenchyme production is further substantiated by increased expression of EMT-relevant genes including TGFβ2, Has2, and periostin. Furthermore, we show that MEKK3 stimulates EMT via a TGFβ2-dependent mechanism. Thus, the activity of MEKK3 is sufficient for developmental EMT in the heart. This knowledge provides a basis to understand how MEKK3 integrates signaling cascades activating endocardial cushion EMT.