Molecular insights into the role of Wnt signaling in supernumerary maxillary incisor formation

BACKGROUND: Sclerostin domain-containing 1 (SOSTDC1) deficiency enhances BMP and Wnt signaling, causing supernumerary teeth formation. Competing hypotheses of this formation at different sites have been proposed, and the underlying molecular mechanisms and cell types remain poorly understood. RESULTS: We examined Sostdc1 knockout effects on spatiotemporal expression of Wnt pathway genes in developing maxillary incisors. In wild type mice, we observed an inverse spatiotemporal expression of Sostdc1 and Wnt10a. The knockout caused ectopic expression of Wnt10a, Wnt6, Lrp4, Dkk1, and Sost and produced a distinct subpopulation of mesenchymal cells. Their spatial transcriptomic analysis and validation of marker genes by in situ mRNA hybridization suggested an unexpected mix of osteogenic and odontogenic differentiation. These cells evolved at the rudimentary labial incisor outgrowth at ~E15.5. At E16.5, their population expanded toward the lingual cervical loop, where a separate supernumerary tooth formed at E17.5. CONCLUSION: The loss of Wnt and BMP signaling inhibition by SOSTDC1 causes aberrant mixed osteogenic and odontogenic differentiation of mesenchymal cells, contributing first to the labial outgrowth and then to the formation of the lingual supernumerary tooth. We hypothesize that this aberrant differentiation underlies the pathology, yet its direct functional role in the supernumerary tooth formation remains to be established.