Department of Genetics, Albert Einstein College of Medicine of Yeshiva University, Price Center 420, 1301 Morris Park Ave, Bronx, NY 10461, USA.
Circ Res. 2011 Jul 8;109(2):183-92. doi: 10.1161/CIRCRESAHA.111.245035. Epub 2011 May 19.
Formation of heart valves requires early endocardial to mesenchymal transformation (EMT) to generate valve mesenchyme and subsequent endocardial cell proliferation to elongate valve leaflets. Nfatc1 (nuclear factor of activated T cells, cytoplasmic 1) is highly expressed in valve endocardial cells and is required for normal valve formation, but its role in the fate of valve endocardial cells during valve development is unknown.
Our aim was to investigate the function of Nfatc1 in cell-fate decision making by valve endocardial cells during EMT and early valve elongation.
Nfatc1 transcription enhancer was used to generate a novel valve endocardial cell-specific Cre mouse line for fate-mapping analyses of valve endocardial cells. The results demonstrate that a subpopulation of valve endocardial cells marked by the Nfatc1 enhancer do not undergo EMT. Instead, these cells remain within the endocardium as a proliferative population to support valve leaflet extension. In contrast, loss of Nfatc1 function leads to enhanced EMT and decreased proliferation of valve endocardium and mesenchyme. The results of blastocyst complementation assays show that Nfatc1 inhibits EMT in a cell-autonomous manner. We further reveal by gene expression studies that Nfatc1 suppresses transcription of Snail1 and Snail2, the key transcriptional factors for initiation of EMT.
These results show that Nfatc1 regulates the cell-fate decision making of valve endocardial cells during valve development and coordinates EMT and valve elongation by allocating endocardial cells to the 2 morphological events essential for valve development.
心脏瓣膜的形成需要早期的心内膜向间质转化（EMT），以产生瓣膜间质，并随后通过心内膜细胞增殖来延长瓣膜小叶。NFATC1（激活的 T 细胞核因子，细胞质 1）在瓣膜心内膜细胞中高度表达，是正常瓣膜形成所必需的，但它在瓣膜发育过程中心包膜细胞命运的作用尚不清楚。
我们的目的是研究 NFATC1 在 EMT 和早期瓣膜伸长过程中心包膜细胞命运决定中的作用。
使用 NFATC1 转录增强子生成了一种新型的瓣膜心内膜细胞特异性 Cre 小鼠系，用于瓣膜心内膜细胞的命运图谱分析。结果表明，NFATC1 增强子标记的瓣膜心内膜细胞亚群不经历 EMT。相反，这些细胞作为增殖群体留在心内膜中，以支持瓣膜小叶的延伸。相比之下，NFATC1 功能的丧失导致 EMT 增强和瓣膜心内膜和间质的增殖减少。胚泡互补测定的结果表明，NFATC1 以细胞自主的方式抑制 EMT。我们通过基因表达研究进一步揭示，NFATC1 抑制 EMT 起始的关键转录因子 Snail1 和 Snail2 的转录。
这些结果表明，NFATC1 在瓣膜发育过程中调节瓣膜心内膜细胞的命运决定，并通过将心内膜细胞分配到对瓣膜发育至关重要的 2 个形态事件中来协调 EMT 和瓣膜伸长。
