Keynote Address: Integration of Signaling Pathways Regulating Toot Organogenesis and Patterning

Abstract Body: Tooth development is controlled by sequential and reciprocal epithelial-mesenchymal inductive interactions and has been used as a model for studying inter-tissue signaling mechanisms regulating mammalian organogenesis. Whereas each of the major signaling pathways, including Bmp, Fgf, Shh, and Wnt signaling, plays critical roles in tooth organogenesis, recent studies show that Wnt and Bmp pathways are the primary determinants of odontogenic epithelial-mesenchymal interactions. However, the molecular mechanisms mediating the crosstalk and integration of these pathways are incompletely understood. Moreover, we recently demonstrated that Bmp4 and the mesenchymal transcription factor Msx1 act in a positive feedback loop to propagate the mesenchymal odontogenic activity to induce sequential tooth formation while the Osr2 transcription factor antagonizes Msx1 function to restrict mammalian tooth formation in a single row. How Msx1 and Osr2 pattern the tooth mesenchyme is not well understood. In this study, we demonstrate that Msx1 and Osr2 regulate, antagonistically, the expression of several secreted Wnt antagonists in the developing tooth mesenchyme. Genetic inactivation and/or pharmacological inhibition of these Wnt antagonists rescued molar tooth morphogenesis in the Msx1 and Bmp4-deficient mice. These data indicate that Osr2 patterns the molar tooth morphogenetic field through integrated regulation of both Bmp4 and Wnt signaling pathways. This work was supported by the National Institutes of Health National Institute of Dental and Craniofacial Research grant DE018401.