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EMT is a process of necessary for formation of 1) the mitral and tricuspid valves in the atrioventricular canal (AVC) and 2) the aortic and pulmonary valves in the outflow tract (OFT) region during development of the heart.
In the endocardium of AVC, Notch1 suppresses BMP2 activity through HEY1/2 activation while it promotes non-invasive EMT through activation of TGFβ2 and SNAIL (SNAI1). BMP2, secreted from the adjacent myocardium, is necessary to trigger a complete invasion of endocardial cells by inducing SNAIL/SLUG (SNAI2) activity in conjunction with Notch1.
SNAIL directly interacts with MMP15 to induce mesenchymal phenotype in the endocardial cells. NFAT2 (NFATC1) acts in a cell-autonomous manner to suppress SNAIL/SLUG activity and inhibit EMT.
In the myocardium of OFT, Jagged1/Notch1 signaling stimulates FGF8 and BMP4 signaling. BMP4, in turn, signals to the endocardium to initiate EMT by stabilizing SNAIL/SLUG and by promoting neural crest cell differentiation, which will further contribute to OFT remodeling and septation.
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