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. Development of the craniofacial region in mammals is a complex and multifactorial process. The focus of our laboratory is to understand the underlying mechanisms involved in the control of craniofacial development since perturbations can lead to birth defects of the head and face. Many signaling molecules have been demonstrated to play critical roles in growth, proliferation, and differentiation of cells that populate the craniofacial region. Included in these are the transforming growth factor (TGF ) and Wnt signaling pathways. Our hypothesis in the current proposal is that the TGF and Wnt signaling pathways exhibit cross-talk leading to unique signaling outcomes not observed with either alone. This hypothesis was developed following our discovery, via a yeast two-hybrid screen of developing craniofacial tissue, that Smads, the central mediators of TGF signaling, interact with dishevelled (Dvl), the proximal cytosolic signaling protein in the Wnt signaling pathway. To examine the role of Wnt signaling in craniofacial development and in particular, the Smad-Dvl interaction, the following specific aims are proposed: 1) characterize the temporal and spatial expression of Wnt signaling components in developing murine embryonic craniofacial tissue and in cultured cells derived from developing craniofacial tissue through Western blot analysis and immunohistochemistry. 2) identify specific protein domains and post-translational modifications that mediate the interaction between Smad and Dvl. 3) examine the effect of the Smad-Dvl interaction on the outcome of signaling from both the TGF and Wnt signaling pathways through the use of transcriptional reporter assays and in vivo signaling through the use of specific inhibitors of TGF and Wnt signaling. These studies will further our understanding of the nature and role of the cross-talk between TGF and Wnt signaling in developing craniofacial tissue.
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