Congenital heart defects occur in nearly 1% of human live births. Outflow tract malformations comprise nearly 40% of these and are lethal if unrepaired. Myocardium at the arterial pole of the heart in the outflow tract and right ventricle derives from a precursor population within the second heart field (SHF). We have discovered that Fibroblast Growth Factor 8 (Fgf8) operates high in a signaling cascade that regulates SHF behavior and the identity of outflow tract myocardial cells. These myocardial cells normally have a 'nonworking' identity with specialized secretory, signaling and cell biologic functions that are critical for outflow tract morphogenesis. In Fgf8 conditional mouse mutants, many aspects of outflow tract myocardial identity are 'mistaken'; the mutant myocardium does not perform the secretory and signaling functions required for downstream endothelial and neural crest behaviors during outflow tract remodeling. Our data support the overriding hypothesis that an autocrine Fgf signaling loop in the SHF is required for outflow tract myocardial precursors to correctly differentiate and achieve their unique identity. The goals of this proposal are to: determine the bases for distinct outflow tract (OFT) phenotypes seen after Fgf8 and Fgf receptor ablation in different temporospatial domains; identify Fgf8-dependent pathways in the SHF and in pharyngeal endoderm; define the identity of SHF-derived myocardial cells in Fgf8 mutant OFT and right ventricle; and discover direct transcriptional targets of Fgf8 effectors in the SHF.
The importance of Fibroblast Growth Factor 8 (Fgf8) function for embryonic cardiovascular development is well established, but the molecular and cellular mechanisms whereby this signaling protein regulates development of the heart are still unknown. The specific research objective is to determine how Fgf8 signaling to heart precursors controls the identity of their progeny in the outflow tract of the heart. We also seek to determine how Fgf8 influences the ability of the myocardial cells to perform signaling and secretory functions that are required for behavior of adjacent cell types during outflow tract development. This research is highly relevant to human birth defects and disease because congenital heart defects occur in nearly 1% of human live births and malformations of the outflow tract comprise nearly 40% of these and are lethal if unrepaired.
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