Type beta transforming growth factor (TGFbeta) and related cytokines including bone morphogenic proteins (BMPs) have bone implicated in diverse aspects of cardiovascular development, dysfunction, and disease including cardiac myogenesis itself, and establishment of the body axes. At present, this case is largely contingent on extrapolation from avian explants and other heterologous model systems. The application of mouse genetics to TGFbeta signaling in vivo has been confounded both by the extensive redundancy among family members, and by maternal rescue (transplacental delivery). Signal transduction for TGFbeta family members involves paired membrane-spanning serine-threonine kinases: type II receptors bind ligand with high affinity, then phosphorylate the type I receptors (activin receptor-like kinases, or ALK proteins), which mediate the downstream effects. Two proposed pathways for TGFbeta and BMP receptor signaling involve the TGFbeta/BMP-activated kinase, and Smad transcription factors; however, it is unknown whether these operate in series or in parallel (i.e., for different subsets of effects). Recently, we have developed a constitutively activated form of the type I receptor, ALK5, directed its expression to the embryonic myocardium, and shown that constitutive signaling by ALK5 arrests looping morphogenesis in mice.
Specific Aims of the present project are: . Using conditional activation of the embryonic-lethal ALK5 gene, to study molecular mechanisms for the block to looping morphogenesis. . To test the functional role of TAK and Smad proteins in signaling by ALK5, in vitro and in vivo. . Using cardiac-restricted expression or conditional induction of Cre recombinase, to test the function of endogenous ALK5 and ALK3 in the early mouse heart.
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