Modulation of tooth regeneration through opposing responses to Wnt and BMP signals in teleosts

Abstract

AbstractMost vertebrates are capable of regenerating entire tooth organs. Tooth regeneration has long been hypothesized to rely on extracellular signals that can influence multiple tooth sites at once. Little is known about which secreted signaling molecules can influence this process. As an entry point, we asked whether fish orthologs of genes known to regulate mammalian hair regeneration have effects on tooth regeneration or total tooth number. We tested whether tooth regeneration could be accelerated by exogenous Wnt signaling (via Wnt10a) or BMP inhibition (Grem2a), and if regeneration rates were slowed by exogenous BMP signaling (Bmp6) or Wnt inhibition (Dkk2). Using two fish species that demonstrate distinct modes of whole tooth regeneration, the threespine stickleback (Gasterosteus aculeatus) and zebrafish (Danio rerio), we found that transgenic overexpression of four different genes changed tooth replacement rates in the predicted direction: Wnt10a and Grem2a increased the tooth replacement rate, while Bmp6 and Dkk2 strongly inhibited replacement tooth formation. Regulation of total tooth number was separable from regulation of regeneration rates. In zebrafish, none of the factors affecting regeneration rate affected the number of distinct tooth families but did sometimes affect total tooth number. In sticklebacks, which do not exhibit clear tooth families, Bmp6 and Dkk2 reduced total tooth number, while Wnt10a and Grem2a did not. These data support a model where different epithelial organs like teeth and hair share genetic inputs driving the timing of whole organ regenerative cycles.