BMPs Regulate the Oft Development via miRNAs

Congenital heart diseases (CHD) are the leading cause of infant mortality and morbidity. Defects of the outflow tract (OFT) make up a large percentage of human CHD. In my study, I focused on the role of Bone morphogenetic protein (BMP) on heart development. I investigated Bmp signaling in OFT development using conditional knocking out Bmps, including Bmp2, -4 and -7. Deletion of Bmp4/7 in second heart field (SHF) results in persistent truncus arteriosus (PTA), which is caused by endothelial to mesenchyme transition (EMT) defect. I found that Vegfa (vascular endothelial growth factor a) is a downstream target of Bmp and miR-17-92. Repression of Vegfa in OFT is important for the proper onset of EMT at E10.5. Further exploration on Bmp2/4/7 mutation indicates that loss of Bmp signal disrupt the smooth muscle differentiation and maintenance. Similar with observations on Marfan syndrome mouse model, Bmp2/4/7 triple CKO embryos exhibited significant upregulation of Tgf-? signal activity. Alternation of SMC feature is likely due to the persistence of Isl-1 expression. Haploinsufficiency of Bmp4 triggered early onset of aorta aneurysm in Fbn-1^(C1039G/+) mice. These data indicate that Bmps not only play an important role in embryonic cardiogenesis, but also are critical for the cell fate differentiation and maintenance in adulthood.