| Congenital cardiac malformations are among the most common birth defects in humans. These include defects in atrioventricular (AV) valves and in the AV septal structures, which separate the systemic and pulmonary circulation. Here, we used a Cre/loxP system in the mouse for endothelial-specific deletion of the Tgf-beta/Bmp type I receptor, Alk2, in order to test whether this receptor is mediating Tgf-beta/Bmp signaling to form endocardial cushions of the AV canal. We show that the Cre recombinase expressed under the control of the Tie2 promoter induced an efficient recombination and inactivation of the Alk2 gene exclusively in the endothelium. Mutant Alk2/Tie2-Cre mice display severe defects both in the atrial and ventricular septation and also in AV valves. We subsequently analyzed the fate of the endothelial cell lineage in Alk2/Tie2-Cre embryos by utilizing the R26R reporter strain. To conclude, Alk2 in endothelial cells is an essential component of the Tgf-beta/Bmp signal transduction complex during the AV cushion morphogenesis and is required for atrial and ventricular septation and valvulogenesis. (Abstract shortened by UMI.)... |
