Activated Epithelial FGF8 Signaling Induces Fused Supernumerary Incisors

Abstract

FGF8, which is specifically expressed in the dental epithelium prior to the E12.5 bud stage, is a key player during odontogenesis, being responsible for the initiation of tooth development. Here, to investigate the impact of persistent FGF8 signaling on tooth development, we forcibly activated FGF8 signaling in the dental epithelium after the bud stage by generating K14-Cre;R26R-Fg8 mice. We found that a unique type of fused supernumerary incisors is formed, although morphologically resembling the features of type II dens invaginatus in humans. Further analysis revealed that ectopically activated epithelial FGF8 alters the cell fate of the incisor lingual outer enamel epithelium, endowing it with odontogenic potential by the activation of several key tooth genes, including Pitx2, Sox2, Lef-1, p38, and Erk1/2, and induces de novo formation of an extra incisor crown lingually in parallel to the original one, leading to the formation of an extra incisor crown and fused with the original incisor eventually. Meanwhile, the overdosed epithelial FGF8 signaling dramatically downregulates the expression of mesenchymal Bmp4, leading to severely impaired enamel mineralization. Based on the location of the extra incisors, we propose that they are likely to be rescued replacement teeth. Our results further demonstrate the essential role of FGF8 signaling for tooth initiation and the establishment of progenitor cells of dental epithelial stem cells during development.