Tinkering with the inductive mesenchyme: Sostdc1 uncovers the role of dental mesenchyme in limiting tooth induction.

Like epithelial organs in general, tooth development involves inductive crosstalk between the epithelium and the mesenchyme. Classically, the inductive potential for tooth formation is considered to reside in the mesenchyme during the visible morphogenesis of teeth, and dental mesenchyme can induce tooth formation even when combined with non-dental epithelium. Here, we have investigated induction of mouse incisors using Sostdc1 (ectodin), a putative antagonist of BMP signaling in the mesenchymal induction of teeth. Deletion of Sostdc1 leads to the full development of single extra incisors adjacent to the main incisors. We show that initially, Sostdc1 expression is limited to the mesenchyme, suggesting that dental mesenchyme may limit supernumerary tooth induction. We test this in wild-type incisors by minimizing the amount of mesenchymal tissue surrounding the incisor tooth germs prior to culture in vitro. The cultured teeth phenocopy the extra incisors phenotype of the Sostdc1-deficient mice. Furthermore, we show that minimizing the amount of dental mesenchyme in cultured Sostdc1-deficient incisors causes the formation of additional de novo incisors that resemble the successional incisor development that results from activated Wnt signaling. Finally, Noggin and Dkk1 prevent individually the formation of extra incisors, and we therefore suggest that inhibition of both BMP and Wnt signaling contributes to the inhibitory role of the dental mesenchyme. Considering the role of mesenchyme in tooth induction and the design of tissue engineering protocols, our work may have uncovered how delicate control of tissue quantities alone influences the outcome between induction and inhibition.