The goal of this proposal is to understand the molecular mechanisms governing development of facial primordia. Wnts are required in craniofacial development for the generation and migration of the cranial neural crest. Based on reporter gene activity, Wnts also play a role in morphogenesis, during the patterned outgrowth of the facial prominences and in the differentiation of epithelial-derived structures. Embryos carrying null mutations in Lef1/TCF4, two enhancers of canonical Wnt signaling, exhibit a dysmorphic frontonasal prominence.
In Specific Aim I the basis for this malformation will be determined using in situ hybridization for Wnt target genes, cellular analyses to determine rates of cell proliferation and differentiation, and histologic assays to characterize the disruption in skeletogenic mesenchyme.
In Specific Aim II in utero gene transfer of a soluble Wnt inhibitor will be utilized to produce a stringent inactivation of the canonical pathway after migration of the cranial neural crest is complete. Embryos treated in this manner will be subject to the same analysis as null embryos. Collectively these data will elucidate the functions of Wnt signaling functions during outgrowth and morphogenesis of the frontonasal prominence. ? ? ?
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| Brugmann, S A; Powder, K E; Young, N M et al. (2010) Comparative gene expression analysis of avian embryonic facial structures reveals new candidates for human craniofacial disorders. Hum Mol Genet 19:920-30 |
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| Brugmann, S A; Kim, J; Helms, J A (2006) Looking different: understanding diversity in facial form. Am J Med Genet A 140:2521-9 |
