This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cleft palate is a common birth defect caused by malformation in secondary palate development. Palate formation requires signaling pathways to function interactively rather than in isolation. However, our understanding of the signaling networks during palate fusion, growth and elevation remains poor. The proposed research will focus on the interactions among major signaling pathways during palate development. TGF-?3 is an essential signaling molecule mediating palate fusion, but the mechanism of action is unknown. We found that TGF-?3 is required for the down-regulation of Jag2 expression during fusion, suggesting TGF-? and Notch pathways function synergistically during fusion. Jag2, IRF6 and IKKa are key regulator factors in preventing pathogenic palate fusion with the tongue and other tissues, and recent studies have revealed the integration of these factors in controlling palate adhesion and fusion. We will pursue two specific aims: I) Interactions between TGF-?3, Notch1/Jag2 during normal and pathogenic palate fusion. We will 1) take a genetic approach to test the hypothesis that TGF-?3 mediates palate fusion by down-regulating Jag2 expression in the MEE; 2) investigate the functional significance of Jag2 down-regulation in MEE during wild type palate fusion. II) Investigation of TGF-? signaling and its interaction with Wnt5a during palate elevation. We will 1) investigate the downstream target genes of Zfhx1a during palate elevation focusing on the genes involving cell migration;2) investigation of the function of TGF-?1,2 during palate by generating TGF-?1,2 double mutants;3) examine the effects of TGF-?s on Wnt5a mediated non-canonical signaling.
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