scpp5 regulates tooth development and injury-induced repair in zebrafish through mineralization and Wnt/β-catenin...

A member of the secretory calcium-binding phosphoprotein (SCPP) family, scpp5 is specifically expressed in zebrafish tooth germ. Although preliminary data indicates that scpp5 deficiency impairs tooth mineralization, its molecular mechanism and role in tooth repair remain unclear. In this study, we generated scpp5^-/- knockout and Tg(hsp70l:scpp5-GFP; cryaa:venus) overexpression zebrafish lines. Tooth germ cells were labeled using Tg(dlx2b:Dendra2-NTR), and a tooth injury model was established via the nitroreductase (NTR)/metronidazole (MTZ) system. Loss-of-function studies showed that scpp5 knockout inhibited tooth mineralization and tooth germ cell development during normal development, attenuated Wnt/β-catenin signaling, downregulated calcium efflux channel gene expression, and suppressed both enameloid and dentin matrix-related genes. Rescue of Wnt pathway activity restored calcium efflux channel and dentin matrix gene expression, but not enameloid matrix gene expression. Gain-of-function studies revealed that scpp5 overexpression did not affect normal tooth development, but during repair after injury, it accelerated mineralization and cell regeneration. Mechanistically, scpp5 overexpression during repair activated Wnt/β-catenin signaling, specifically enhancing calcium channel and dentin matrix gene expression, without affecting enameloid matrix gene expression. Collectively, these findings demonstrate that scpp5 promotes tooth mineralization during normal development via Wnt/β-catenin-dependent regulation of both enameloid and dentin matrix genes, whereas during injury repair, scpp5 facilitates regeneration by selectively activating Wnt/β-catenin to drive dentin matrix and calcium channel gene expression, independent of enameloid matrix genes.