CHARACTERIZATION & MODIFICATION OF CARDIAC NEURAL CREST

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Multi-disciplinary studies of chick embryos that neural crest ablation have shown that myocardial function is altered prior to the time that neural crest cells would be expected to reach the heart in intact embryos. At the time when myocardial dysfunction can first be seen, the cardiac neural cress cells are in contact with the dorsolateral margin of the pharynx. We have recently found that isolated pharyngeal endoderm can cause similar changes in cultured myocardium. The effect can be blocked by a polyclonal neutralizing antibody to FGF. These observations have led to the hypothesis that 1) an interaction of neural crest cells with endoderm is required for suppression of an FGF-like signal that leads to abnormal myocardial development in neural crest cells to suppress the endodermally-derived signal. The hypotheses will be tested first by localizing expression of FGF ligands and receptors in neural crest, endoderm, and myocardium and then in tissue recombinations of neural crest and/or endoderm with myocardium in vitro. Various techniques will be used to interfere with FGF signaling in the tissue recombinations and in explant cultures. Various techniques will be used to interfere with FGF signaling in the tissue recombinations and in explant cultures. Neural crest ablations and back-transplantations will be used to modify expression of FGF modulating factors and to interfere with FGF signaling in intact embryos. Finally, we will apply excess retinoic acid to neural crest cells to alter the ability of neural crest to modulate the FGF signaling mechanism. The experiments proposed will elucidate a previously unrecognized function of cardiac neural crest cells and characterize the interactions of neural crest cells with pharyngeal endoderm. These interactions appear to be critical for normal myocardial development and in their absence, myocardial developmental history is altered. We believe that this may lead to the high mortality in children with neural crest-related heart defects even after surgical repair.