Wnt/beta-catenin signaling directs multiple stages of tooth morphogenesis

Wnt/beta-catenin signaling plays key roles in tooth development, but how this pathway intersects with the complex interplay of signaling factors regulating dental morphogenesis has been unclear. We demonstrate that Wnt/beta-catenin signaling is active at multiple stages of tooth development. Mutation of p-catenin to a constitutively active form in oral epithelium causes formation of large, misshapen tooth buds and ectopic teeth, and expanded expression of signaling molecules important for tooth development. Conversely, expression of key morphogenetic regulators including Bnip4, Msx1, and Msx2 is downregulated in embryos expressing the secreted Writ inhibitor Dkk1 which blocks signaling in epithelial and underlying mesenchymal cells. Similar phenotypes are observed in embryos lacking epitbelial beta-catenin, demonstrating a requirement for Writ signaling within the epithelium. Inducible Dkk1 expression after the bud stage causes formation of blunted molar cusps, dowmegulation of the enamel knot marker p21, and loss of restricted ectodin expression, revealing requirements for Writ activity in maintaining secondary enamel knots. These data place Wnt/beta-catenin signaling upstream of key morphogenetic signaling pathways at multiple stages of tooth development and indicate that tight regulation of this pathway is essential both for patterning tooth development in the dental lamina, and for controlling the shape of individual teeth. (c) 2007 Elsevier Inc. All rights reserved.