Wnt/β-catenin interacts with the FGF pathway to promote proliferation and regenerative cell proliferation in the zebrafish lateral line neuromast

Wnt and FGF are highly conserved signaling pathways found in various organs and have been identified as important regulators of auditory organ development. In this study, we used the zebrafish lateral line system to study the cooperative roles of the Wnt and FGF pathways in regulating progenitor cell proliferation and regenerative cell proliferation. We found that activation of Wnt signaling induced cell proliferation and increased the number of hair cells in both developing and regenerating neuromasts. We further demonstrated that FGF signaling was critically involved in Wnt-regulated proliferation, and inhibition of FGF abolished the Wnt stimulation-mediated effects on cell proliferation, while activating FGF signaling with basic fibroblast growth factor (bFGF) led to a partial rescue of the proliferative failure and hair cell defects in the absence of Wnt activity. Whole-mount in situ hybridization analysis showed that the expression of several FGF pathway genes, including pea3 and fgfr1, was increased in neuromasts after treatment with the Wnt pathway inducer BIO. Interestingly, when SU5402 was used to inhibit FGF signaling, neuromast cells expressed much lower levels of the FGF receptor gene, fgfr1, but produced increased levels of Wnt target genes, including ctnnb1, ctnnb2, and tcf7l2, while bFGF treatment produced no alterations in the expression of those genes, suggesting that fgfr1 might restrict Wnt signaling in neuromasts during proliferation. In summary, our analysis demonstrates that both the Wnt and FGF pathways are tightly integrated to modulate the proliferation of progenitor cells during early neuromast development and regenerative cell proliferation after neomycin-induced injury in the zebrafish neuromast.