Tail Fin Regeneration in Zebrafish: The Role of Non-canonical Crosstalk Between STAT3 and Vitamin D Pathway

Stat3 is a transcription factor with a key role in cell proliferation and migration. Using the stat3^-/- zebrafish line we showed that the stat3 genetic ablation results in a marked decrease of tail fin regrowth, demonstrating that this transcription factor is fundamental in the regeneration process. Stat3 activity is finely modulated by post-translational modifications that occur in several residues of the protein (i.e., Y705 and S727 phosphorylation), with tissue-specific effects. Using the newly generated stat3^S→A751 zebrafish line, we demonstrated that the Stat3 phosphorylation in the non-canonical S751 site (homologous of mammalian serine 727) is required for the regeneration of tail fin in both larval and adult stage, even if this phosphorylation has largely been reported to have marginal roles in Stat3 activity. Our analysis showed that both stat3^-/- and stat3^S→A751 mutant zebrafish lines have alterations in the expression of genes involved in epithelial and bone tissue regeneration, including genes coding for the vitamin D signaling pathway. Interestingly, the reduced regeneration activity in zebrafish stat3^-/- and stat3^A751/A751 larvae is partially rescued by vitamin D treatment. Together, these results reveal a Stat3-vitamin D co-regulatory mechanism during zebrafish tail fin regeneration.