Functional Roles of Wnt and Snail2 Target Genes in Neural Crest Development

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The general theme of my research career has been to determine the molecular basis by which the Wnt signaling pathway activates expression of target genes and subsequently affects the generation of a particular cell type, in a context-dependent and temporal manner. The Wnt signaling pathway and its components are used reiteratively throughout embryonic development and in mature tissues during the transformation of normal cells to cancerous ones, demonstrating the importance of this pathway. Wnt signaling plays a significant role in the development of the neural crest, a population of migratory cells that helps pattern the embryo. Because of its contribution to embryonic structures, defects in neural crest development give rise to multiple syndromes, diseases, and cancers, including Axenfeld-Rieger, Di George and Treacher-Collins syndromes, and neurofibromatosis. To further understand how Wnt signaling regulates neural crest development, I have performed a screen to identify novel targets of Wnt signaling involved in this process. Furthermore, investigation into the role of known Wnt target genes, such as Snail2 (Slug) allows me to elucidate how Snail2 regulates expression of its molecular targets in the context of neural crest development. Embryological and biochemical methods will be employed to determine the functional significance of these targets and their mode of regulation by Wnt. Overall, these approaches will provide me with a group of candidate molecules that will likely function in the generation of structures derived from the neural crest, such as the craniofacial skeleton and peripheral nervous system, as well as provide insight into the development of neural crest-derived cancers. In summary, my long-term research and career objectives include conducting mentored research (in the final years of my postdoc) and independent research (as a principal investigator) to elucidate the molecular mechanism underlying Wnt signaling during the development of the neural crest, and applying this knowledge to human development as a whole. This research is relevant to public health because of the biological significance of the neural crest to the proper formation of human bodies, such as the bones of the face, nerves and skin pigment cells. How neural crest cells properly become such diverse structures can help us comprehend what happens when neural crest development is impaired, and human syndromes and cancers arise.