Activin Receptor-Like Kinase-2 in Cardiac Morphogenesis

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DESCRIPTION (provided by applicant): Malformations of the cardiovascular system are among the most common birth defects in humans. Members of the evolutionary conserved TGF-beta superfamily of secreted growth factors have been shown to play important roles during normal heart development. They all signal through several different type I receptors (called Activin Receptor-Like Kinases; Alks), which are the primary determinants of signaling specificity. Among these receptors AIk2 is of particular interest, since it appears that AIk2 mediates both BMP, Activin and TGFbeta signals. AIk2 is strongly expressed in the heart, and our preliminary experiments demonstrate that AIk2 is required for normal cardiac development. Therefore, we hypothesize that AIk2 plays a key role in cardiac outflow tract development by regulating differentiation, proliferation and/or survival of cardiac neural crest cells. We will test this hypothesis by three Specific Aims by utilizing a genetically manipulated mouse strain we recently developed that allows inactivation of AIk2 specifically in neural crest cells. In Aim 1, defects in valves, septa and outflow tracts will be analyzed in detail. In Aim 2, we will define the specific process controlled by AIk2 during cardiac outflow tract morphogenesis, and in Aim 3 we will identify the relevant downstream signaling molecules, Smads, and transcriptional targets in the AIk2-mediated pathway. Our experimental strategy will allow us to determine the biological role of AIk2 in cardiac outflow tract development. The results of these studies are likely to be of critical importance in attempting to reach our long-term goal to understand the molecular basis of life-threatening congenital heart defects in humans.