RXR-ALPHA REGULATES CARDIAC NEURAL CREST CELL MIGRATION

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The cardiac neural crest cells are necessary for proper heart formation and maturation of individual cardiac chambers. In particular, these cells are involved in the formation of the outflow tract and aortic arch arteries. Requirements for these cells has been best demonstrated by neural crest ablation studies in the chick which results in a variety of cardiac malformations including PTA, VSD, and DORV. Interestingly, these defects resemble various forms of congenital heart disease seen in the clinical setting. In addition, both an excess of retinoic acid (RA) or vitamin A- deficiency leads to similar phenotypes suggesting that RA may also be involved in cardiac neural crest migration and/or differentiation. Furthermore, it has been shown that mutations to the RA receptor RXRalpha lead to similar cardiac phenotypes suggesting that RA signaling pathways regulating the cardiac neural crest cell lineage are mediated via RXRalpha. Therefore the hypothesis under investigation states that outflow tract defects detected in the RXRalpha mutant result from defects in cardiac neural crest cell migration. Two specific aims have been designed to test this hypothesis. (1) To determine if the outflow tract defects found in the RXRalpha deficient embryos is the result of defects in cardiac neural crest cell migration by (a) molecular marker analysis and (b) indicator mouse lines; (2) To determine if the defect in neural crest cell migration is cell autonomous or non-cell-autonomous by (a) co-localization of RXRalpha to the cardiac neural crest cells, (b) neural tube explant cultured and (c) analyzing cardiac neural crest cell migration and outflow tract defects in mice harboring a cardiac neural crest restricted deficiency in RXRalpha.