A field of myocardial-endocardial NFAT signaling underlies heart valve morphogenesis
A field of myocardial-endocardial NFAT signaling underlies heart valve morphogenesis
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DOI：
10.1016/j.cell.2004.08.010
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发表时间：
2004-09-03
期刊：
影响因子：
64.5
通讯作者：
Crabtree, GR
中科院分区：
文献类型：
--
作者：
Chang, CP;Neilson, JR;Crabtree, GR
组成脊椎动物心脏瓣膜的精致叶子对我们的生存是必不可少的。瓣膜形成异常是人类最常见的严重先天性缺陷。尽管它们很重要，但人们对阀门的开发知之甚少。我们发现，小鼠心脏瓣膜形态发生的启动需要钙调神经磷酸酶/NFAT来抑制预期瓣膜形成部位下的心肌中血管内皮生长因子的表达。在E9，这种对血管内皮生长因子的抑制是心内膜细胞向间充质细胞转化所必需的。后来，在E11，第二波钙调神经磷酸酶/NFAT信号需要在心内膜中，毗邻NFAT作用的早期心肌部位，以指导瓣膜延长和细化。因此，NFAT信号在瓣膜形态发生区内从心肌到心内膜依次起作用，启动和维持胚胎瓣膜的形成。这一机制也适用于斑马鱼，表明钙调神经磷酸酶/NFAT信号在脊椎动物心脏瓣膜形态发生中具有保守的作用。
The delicate leaflets that make up vertebrate heart valves are essential for our moment-to-moment existence. Abnormalities of valve formation are the most common serious human congenital defect. Despite their importance, relatively little is known about valve development. We show that the initiation of heart valve morphogenesis in mice requires calcineurin/NFAT to repress VEGF expression in the myocardium underlying the site of prospective valve formation. This repression of VEGF at E9 is essential for endocardial cells to transform into mesenchymal cells. Later, at Ell, a second wave of calcineurin/NFAT signaling is required in the endocardium, adjacent to the earlier myocardial site of NFAT action, to direct valvular elongation and refinement. Thus, NFAT signaling functions sequentially from myocardium to endocardium within a valvular morphogenetic field to initiate and perpetuate embryonic valve formation. This mechanism also operates in zebrafish, indicating a conserved role for calcineurin/NFAT signaling in vertebrate heart valve morphogenesis.