The vertebrate skull is a complex structure that functions as a rigid and protective barrier in addition to adjusting to the expansion of the developing brain. The growth of calvarial bones begins as mesenchymal cell condensations which proliferate and ultimately differentiate into matrix-synthesizing osteoblasts. The homeobox transcription factor Msx2 plays a direct role in tissue interactions that pattern the cranium. Mutations in the human MSX2 gene are associated with Boston-type craniosynostosis while functional haploinsufficiency of MSX2 causes defects in skull ossification. The molecular mechanisms of skull patterning and morphogenesis are poorly understood. Among the signaling molecules expressed in tissues involved in patterning of calvarial bones are bone morphogenetic proteins (BMPs) which regulate the expression of Msx2. Lack of calvarium in the """"""""congenital hydrocephalus"""""""" mouse is caused by a mutation in the fork head transcription factor FoxC1 which is required for Msx2 induction by BMP. The fundamental goal of this project is to unravel the mechanism whereby FoxC1, an essential transcription factor for normal calvarial development, modulates BMP signaling. The requested training support from NIDCR will permit the applicant to determine if a direct interaction exists between Smads and FoxC1, to define the DMA target site preference for FoxC1 and to determine the role of phosphorylation in BMP2-induced FoxC1-dependent Msx2 transcriptional regulation. Long-term goals of the candidate include: to contribute to the advancement of research in craniofacial bone biology and BMP signaling and to teach in a dental school setting. Relevance: The regulation of MSX2, an essential gene involved in skull and suture development, by Bone Morphogenetic Proteins (BMPs) requires functional FoxC1 protein. Mutations in FoxC1 have been identified in patients with hydrocephalus in addition to dental and anterior segment of the eye abnormalities. Our goal is to elucidate the mechanism through which FoxC1 participates in the BMP regulation of MSX2.
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