Precise levels of Tbx20 are necessary for cardiac chamber and valve formation in vivo in mice

Abstract

Tbx20 gain-of-function mutations in humans have been associated with a wide spectrum of cardiovascular abnormalities. Here, Nkx2.5 and βMHCCre mice are used, respectively, for early and late overexpression of Tbx20 in cardiomyocytes of transgenic animals. Nkx2.5Cre mediated overexpression of Tbx20 resulted in inhibition of mature chamber myocardium formation associated with reduced proliferation and increased expression of p21. In contrast, βMHCCre-mediated overexpression of Tbx20 in differentiated cardiomyocytes resulted in altered heart morphology with increased proliferation. Increased expression of Tbx5, Connexins 40 and 43 also is detected in myocardium overexpressing Tbx20, consistent with altered expression of conduction system genes. In developing heart valves, Tie2Cre-mediated overexpression of Tbx20 results in abnormalities in endocardial cushion (EC) development associated with reduced proliferation and increased expression of p21. Tbx20 overexpression in mutant embryos also results in reduced expression of several endothelial genes, including NFATc1, Flk1 and VE-Cadherin in endocardial cushion endothelium. These data implicate Tbx20 as a critical regulator of cellular proliferation in early and differentiated cardiomyocytes and also in valve endothelial cells. This work is supported by an AHA Post-Doctoral Fellowship (0825627D) to SC and NIH HL082716 and HL094319 to KEY. Grant Funding Source: National Institute Of Health (NIH) and American Heart Institute (AHA)