Induction of new tooth formation in adult oral ectoderm

Supernumerary teeth have been found in certain cases of human patients, including Gardner's syndrome with mutations in the adenomatous polyposis coli (APC) gene. APC is an inhibitor of Wnt signaling pathway. Loss of APC is associated with stabilization of cytosolic b-catenin leading to its migration to the nucleus and activating Wnt target genes. We reported previously that K14-Cre mediated inactivation of Apc in the mouse oral ectoderm (K14Cre;Apc^cko/cko) generated multiple supernumerary teeth in the jaw. In this study, we analyzed in detail the tooth phenotypes of K14Cre;Apc^cko/cko mice, and noticed that although all the K14Cre;Apc^cko/cko pups die before postnatal day 18, the number of supernumerary teeth dramatically increase with age. Objectives: The purpose of this study was to determine whether adult oral epthelium retains tooth-forming potential. Methods: We inactivated Apc gene in adult mice expressing the floxed Apc in conjection with a K14Cre ER^TM allele. We also activated Wnt signaling in adult tissues by using K14CreER^TM;b-catenin^Ĉex3fl/+ mice. K14CreER^TM;Apc^CKO/CKO and K14CreER^TM;b-catenin^Ĉex3fl/+ mice were injected intraperitoneally with 4-hybroxitamoxifen (4-OHT) for 5 consecutive days to activate CreER^TM, then sacrificed 2-3 weeks later after the last injection. Results: Administration of 4-OHT can induce extra teeth at the molar region at postnatal 5 days old, and even the Hertwig's epithelial root sheet can form extra tooth buds. Large numbers of supernumerary teeth can still be induced at the incisor region at 10-month-old age. Conclusions: These results indicate that Wnt stimulates while APC inhibits odontogenic potential throughout adult oral ectoderm. Adult oral ectoderm remains responsive to APC loss of function or b-catenin gain-of-function, and is still able to form new teeth. Since the development of human teeth continues several years after birth and retains dental lamina or dental stem cells in their jaws, these data may be used to develop new teeth in humans.