POTENTIAL MSXL DOWNSTREAM GENES IN TOOTH DEVELOPMENT

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The developing molar tooth germ provides a powerful developmental system for identifying the genetic pathways involved in mammalian organogenesis. Mutations in Msx1 are responsible for anodontia in both humans and mouse. In mouse Msx1 mutants, arrest of tooth development occurs at the bud stage when tooth inductive potential normally shifts from dental epithelium to dental mesenchyme. The shift of odontogenic potential coincides with the shift of expression of Bone morphogenicetic protein-4 (Bmp4), a TGFbeta superfamily member, from epithelium to mesenchyme. Msx1 is required for this shift in Bmp4 expression to the dental mesenchyme; in Msx1 mutants dental epithelial Bmp4 expression is preserved, but that in the dental mesenchyme is absent. FGFs constitute another family of growth factors which potentially play an analogous role in the signaling cascade between dental epithelium and mesenchyme. I have recently shown that epithelial FGFs like FGF8 can induce Fgf3 expression in dental mesenchyme and that this induction requires Msx1. These results indicate that FGF8, like BMP4, constitutes an epithelial inductive signal which can induce the expression of its respective family members in dental mesenchyme in an Msx1-dependent manner. Nevertheless, the role of BMP4 and FGF3 as Msx1 downstream signals during tooth development and the mechanism by which Msx1 functions to regulate transcription of their respective genes remains unknown. The specific aims of this proposal are twofold. First I will determine the developmental role of the Msx1-downstream signals BMP4 and FGF3. For this purpose, in vitro and in vivo techniques will be employed to address the hypothesis that BMP4, alone or in combination with FGF3, can bypass the Msx1 requirement and rescue the Msx1 tooth phenotype. Second, the hypothesis that Msx1 interacts with accessory proteins in order to confer sufficiency for activation of its downstream genes will be addressed in the second specific aim of this proposal. Both biochemical and genetic experiments will be used to address this latter hypothesis.