The broad aim of this project is to dissect genetically the role of Tbx1 during pharyngeal and cardiovascular development. Tbx1 is required for the development of the pharyngeal arches and pouches and is a key candidate gene for DiGeorge Syndrome. Developmental defects of the embryonic pharyngeal apparatus are the basis of many human birth defects, including different types of congenital heart abnormalities. This project is driven by a model in which Tbx1 has an early, cell-autonomous function in pharyngeal segmentation and a later, cell non-autonomous function in the growth and remodeling of the pharyngeal arch arteries. The early function is proposed to be dependent upon genetic control of Tbx1 in the endoderm, and the late function is proposed to be dependent upon genetic interactions between Tbx1 and the fibroblast growth factor (FGF) signaling pathway. To address this model, 4 specific aims are proposed: 1) To distinguish the late from the early roles of Tbx1 by inactivating the gene in a time-controlled manner. 2) To establish the role of an endoderm enhancer of Tbx1 during pharyngeal morphogenesis, by modifying the enhancer in the endogenous gene. 3) To understand the role of the FGF signaling in the pathogenesis of the Tbx1 mutant phenotype. This will be achieved by a) testing the ability of FGF activity to rescue the Tbx1 mutant phenotype b) disrupting T-box binding sites from the Fgf8 and Fgf10 genes, and c) testing the ability of Tbx1 to activate Fgf genes ectopically. 4) To understand the role of Tbx1 in the alignment of the outflow tract using tissue-specific deletion. It is proposed that this role is also mediated by the FGF signaling. Published and preliminary data support the proposed model, and the collection of Tbx1 mutant alleles already generated and that will be generated with this project, should provide a unique opportunity to dissect the role of Tbx1 in cardiovascular and pharyngeal development.
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