Abstract
In common with most mammals, humans form only two dentitions during their lifetime. Occasionally, supernumerary teeth develop in addition to the normal complement. Odontoma represent a small group of malformations containing calcified dental tissues of both epithelial and mesenchymal origin, with varying levels of organization, including tooth-like structures. The specific cell type responsible for the induction of odontoma, which retains the capacity to re-initiate de novo tooth development in postnatal tissues, is not known. Here we demonstrate that aberrant activation of WNT signaling by expression of a non-degradable form of β-catenin specifically in SOX2-positive postnatal dental epithelial stem cells is sufficient to generate odontoma containing multiple tooth-like structures complete with all dental tissue layers. Genetic lineage-tracing confirms that odontoma form in a similar manner to normal teeth, derived from both the mutation-sustaining epithelial stem cells and adjacent mesenchymal tissues. Activation of the WNT pathway in embryonic SOX2-positive progenitors results in ectopic expression of secreted signals that promote odontogenesis throughout the oral cavity. Significantly, the inductive potential of epithelial dental stem cells is retained in postnatal tissues, and up-regulation of WNT signaling specifically in these cells is sufficient to promote generation and growth of ectopic malformations faithfully resembling human odontoma.
Highlights
Throughout postnatal OE leads to ectopic tooth formation in both incisor and molar regions, depending upon age[9,12]
We provide evidence that pathway activation in SOX2-positive progenitor/stem cells within the OE is sufficient to generate this phenotype in mice, providing a potential mechanism for the formation of odontoma in human populations
Genetic lineage tracing revealed that mature odontoma-like structures only had a partial contribution of cells derived from those sustaining the mutation, suggesting a paracrine induction of surrounding tissues
Summary
Throughout postnatal OE leads to ectopic tooth formation in both incisor and molar regions, depending upon age[9,12]. These experiments have demonstrated the importance of appropriately regulated WNT signaling during murine odontogenesis; they have not identified the OE progenitor cell population through which, this pathway may act. By genetically expressing constitutive-active Ctnnb[1] in Sox2-expressing SCs, we have modelled supernumerary tooth formation in the adult murine dentition; the formation of odontoma in the mandible and maxilla, and established that WNT pathway up-regulation in dental SCs reinstates the inductive properties that occur during early tooth development
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