Developmental abnormalities in endocardial cushions frequently contribute to congenital heart malformations including septal and valvular defects. While compelling evidence has been presented to demonstrate that members of the TGF-beta superfamily are capable of inducing endothelial-to-mesenchymal transdifferentiation in the atrioventricular canal, and thus play a key role in formation of endocardial cushions, the detailed signaling mechanisms of this important developmental process, especially in vivo, are still poorly known. Several type I receptors (ALKs) for members of the TGF-beta superfamily are expressed in the myocardium and endocardium of the developing heart, including the atrioventricular canal. However, analysis of their functional role during mammalian development has been significantly complicated by the fact that deletion of the type I receptors in mouse embryos often leads to early embryonal lethality. Here, we used the Cre/loxP system for endothelial-specific deletion of the type I receptor Alk2 in mouse embryos. The endothelial-specific Alk2 mutant mice display defects in atrioventricular septa and valves, which result from a failure of endocardial cells to appropriately transdifferentiate into the mesenchyme in the AV canal. Endocardial cells deficient in Alk2 demonstrate decreased expression of Msx1 and Snail, and reduced phosphorylation of BMP and TGF-beta Smads. Moreover, we show that endocardial cells lacking Alk2 fail to delaminate from AV canal explants. Collectively, these results indicate that the BMP type I receptor ALK2 in endothelial cells plays a critical non-redundant role in early phases of endocardial cushion formation during cardiac morphogenesis.

Background The definitive endoderm arises as a naive epithelial sheet that produces the entire gut tube and associated organs including the liver, pancreas and lungs. Murine explant studies demonstrate that Fibroblast Growth Factor (FGF) signaling from adjacent tissues is required to induce hepatic gene expression from isolated foregut endoderm. The requirement of FGF signaling during liver development is examined via small molecule inhibition during whole embryo culture. Results Loss of FGF signaling prior to hepatic induction results in morphological defects and gene expression changes that are confined to the anterior liver bud. In contrast the posterior portion of the liver bud remains relatively unaffected. Because FGF is thought to act as a morphogen during endoderm organogenesis, the ventral pancreas was also examined after FGF inhibition. Although the size of the ventral pancreas is not affected, loss of FGF signaling results in a significantly higher density of ventral pancreas cells. Conclusions The requirement for FGF-mediated induction of hepatic gene expression differs across the anterior-posterior axis of the developing liver bud. These results underscore the importance of studying tissue differentiation in the context of the whole embryo.

Background: Congenital cardiovascular diseases are the most common form of birth defects in humans. A substantial portion of these defects has been associated with inappropriate induction, migration, differentiation and patterning of pluripotent cardiac neural crest stem cells. While TGF-β-superfamily signaling has been strongly implicated in neural crest cell development, the detailed molecular signaling mechanisms in vivo are still poorly understood.