Molecular and Cellular Basis of Pharyngeal Pouch Development

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DESCRIPTION (provided by applicant): Facial epithelia, including the pharyngeal pouches, are important signaling centers that organize development of the head. Defects in pouch formation in human birth defects such as DiGeorge Syndrome result in a variety of developmental abnormalities of the facial skeleton, heart, and glands (e.g. parathyroid and thymus). However, we still know little about the genetic control and cellular behaviors underlying pouch formation. The long-term goal of this proposal is to understand how the DiGeorge Syndrome gene Tbx1 interacts with Fgf and Wnt signaling pathways to precisely control the epithelial transitions that drive pouch formation. In this proposal, we use innovative transgenic and mutant tools in zebrafish to assess the function of developmental genes in the pre-pouch endoderm. We combine this with time-lapse imaging of pouch development in living embryos, which allows us to understand how these genes control specific pouch cell behaviors. Zebrafish is ideally suited for these studies as pouch development is highly conserved with humans, yet zebrafish is the only vertebrate system in which high-throughout transgenic studies and single-cell- resolution time-lapse imaging are practical. Positive findings from this work will elucidate how Tbx1 acts upstream to activate Wnt and Fgf signaling cascades that drive pouch development. In particular, Wnt pathway genes will represent novel candidates for underlying and/or modifying human birth defects such as DiGeorge and Pfeiffer Syndromes. As branching of the embryonic endoderm generates not only pouches but also the liver, pancreas, lung, and other organs, lessons learned from our studies will also have general implications for understanding the initial formation of many important endodermal organs.