The long-term objective of this proposal is to understand stem cell commitment and differentiation to a myocardial lineage. Our group has recently discovered a previously unknown secondary heart field that produces the myocardium of the definitive outflow tract in chick embryos. We have found that failure of outflow lengthening by addition of myocardial cells from the secondary heart field during cardiac looping results in dextroposed aorta. The overall hypothesis of the application is that the process of stem cell commitment to a myocardial lineage is common to all myocardial progenitor populations. The specific hypotheses to be tested in these experiments are: (1) The secondary heart field has an origin distinct from the primary heart field. This will be determined using three state-of-the-art cell tracing techniques in chick embryos. (2) Commitment of cells in the secondary heart field to the myocardial lineage is induced by members of the same growth factor families that induce myocardial commitment in the primary heart fields. TGFbeta and FGF family members are expressed in proximity to the outflow tract during its lengthening. Specific members of this family, including FGF-8 and BMP-2, will be manipulated in a variety of ways to determine their role in inducing differentiation of secondary heart field cells into myocardium. The studies proposed will establish the developmental history of the secondary heart field. Furthermore, because the outflow myocardium is critical for correct septation of the arterial pole of the heart, these studies will enhance our knowledge of normal development of the definitive outflow myocardium, and will provide new insights into the basis of conotruncal malformations. ? ?
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