Apc inhibition of Wnt signaling regulates supernumerary tooth formation during embryogenesis and throughout adulthood

Abstract

The ablation of Apc function or the constitutive activation of β-catenin in embryonic mouse oral epithelium results in supernumerary tooth formation, but the underlying mechanisms and whether adult tissues retain this potential are unknown. Here we show that supernumerary teeth can form from multiple regions of the jaw and that they are properly mineralized, vascularized, innervated and can start to form roots. Even adult dental tissues can form new teeth in response to either epithelial Apc loss-offunction or β-catenin activation, and the effect of Apc deficiency is mediated by β-catenin. The formation of supernumerary teeth via Apc loss-of-function is non-cell-autonomous. A small number of Apc-deficient cells is sufficient to induce surrounding wild-type epithelial and mesenchymal cells to participate in the formation of new teeth. Strikingly, Msx1, which is necessary for endogenous tooth development, is dispensable for supernumerary tooth formation. In addition, we identify Fgf8, a known tooth initiation marker, as a direct target of Wnt/β-catenin signaling. These studies identify key mechanistic features responsible for supernumerary tooth formation.

Signaling Networks Regulating Tooth Organogenesis and Regeneration, and the Specification of Dental Mesenchymal and Epithelial Cell Lineages

“…A similar phenotype is seen in mice when Wnt signaling is activated in the epithelium either by deletion of APC or stabilization of b-catenin (Fig. 5F-H) (Järvinen et al 2006;Liu et al 2008;Wang et al 2009). Sp6 2/2 (Epiprofin) mutants have a similar phenotype but this gene has not been associated with human conditions (Nakamura et al 2008;Wang and Fan Figure 5.…”

“…2B) (Jernvall et al 2000). Wnts are important upstream regulators of enamel knots as shown by the requirement of Lef1 for Fgf4 expression in the enamel knot (Kratochwil et al 2002) and the induction of new enamel knots and placodes by forced activation of Wnt/b-catenin signaling in oral epithelium (Järvinen et al 2006;Wang et al 2009). More than a dozen different signal molecules belonging to all four conserved signal families are locally expressed in the primary and secondary enamel knots.…”

“…Activation of Wnt signaling in the epithelium induces supernumerary placodes throughout the surface epithelium and they give rise to various epithelial appendages. Yet extra teeth form only in the region of dental arches and mostly in connection with other teeth (Järvinen et al 2006;Wang et al 2009). These observations indicate that the odontogenic competence is present only in the oral region.…”

“…In addition to Shh, which is restricted to the dental lamina, many Wnt ligands are expressed in the oral epithelium (Sarkar and Sharpe 1999). Wnt/b-catenin signaling regulates Fgf8 expression in the early epithelium (Wang et al 2009), and placodes do not form in mice overexpressing the Wnt inhibitor Dkk1 (Andl et al 2002). Bmp4 and Fgf8 are expressed in the jaw epithelium in overlapping patterns before any morphological sign of tooth development.…”

Spatially restricted dental regeneration drives pufferfish beak development

“…Wnt signaling has been identified as a key regulator of dental regeneration in polyphyodonts, with its up-regulation leading to ectopic tooth germ formation in the dental lamina of snakes (35). Ectopic Wnt signaling also leads to supernumerary teeth in mice (36), with upregulation specifically in Sox2 + dental epithelial cells sufficient to generate odontomas (37). Furthermore, active Notch, Hh, Bmp, Fgf, and Wnt signaling during dental differentiation and morphogenesis further highlights the conservation of developmental signaling during tooth development across gnathostome vertebrates.…”