Congenital heart disease is the most common of all birth defects, and results from a """"""""gross structural abnormality of the heart or intrathoracic great vessels"""""""". To understand the etiology of congenital heart disease, it is of utmost importance to understand normal heart development. We have recently discovered a new paradigm for heart development, through studies of a LIM-homeodomain transcription factor, islet1 (isl1). Mice homozygous null for isl1 die embryonically, with strikingly abnormal hearts. Detailed histological and marker analysis has demonstrated that isl mutant hearts are lacking an outflow tract, right ventricle, and have relatively little atrial tissue, isl is not expressed in the primary cardiac crescent but rather is expressed in a population of adjacent mesendodermal cells. Surprisingly, lineage analysis of isl expressing cells has demonstrated that descendents of isl give rise to the outflow tract, right ventricle, and a majority of atrial cells in the embryonic heart. Together, our results necessitate a redefinition of the secondary heart field, as being far more extensive than previously suspected, islet expression both marks this redefined secondary heart field, and is required for the secondary heart field to give rise to major segments of the embryonic heart. In isl mutants, there appear to be fewer islet expressing cells, and expression of a number of fibroblast and bone morphogenetic protein growth factors is downregulated in the secondary heart field. These observations suggest the hypothesis that islet dictates growth, survival, migration, and specification of cardiac progenitors in the secondary heart field by its regulation of FGF and BMP growth factor pathways. The proposed studies will investigate this hypothesis by further studies of the isl mutant phenotype, and selective ablation of FGF and BMP receptors within the secondary heart field. Our experiments will yield novel insight into pathways required for maintenance of the cardiogenic stem cell state, and pathways required for specification of distinct lineages within the heart which arise from secondary heart field.
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