Wnt5a Is Critical for the Maintenance of Cell Proliferation and Differentiation in Xenopus Tadpole Tail Regeneration.

Wnt signaling is essential for tissue and organ regeneration in animals such as amphibians, and several Wnt ligands are highly expressed in regenerating tissues. However, little is known about the specific role played by each ligand and their relative contribution to regeneration processes. Here, we show that Wnt5a plays critical roles in cell proliferation and differentiation during Xenopus tadpole tail regeneration. CRISPR/Cas9-mediated knock-out (KO) of the wnt5a gene in Xenopus tadpoles caused a delay in tail regeneration. Expression of wnt5a is induced after wound healing in regenerating tails and is positively regulated by the early injury response genes junb and inhba, which are required for the initiation of regenerative cell proliferation. Interestingly, in wnt5a KO tadpoles, cell proliferation initiated by JunB and InhibinβA was reduced at late stages of tail regeneration, suggesting an essential role of Wnt5a in the maintenance of regenerative cell proliferation. Moreover, differentiation of the notochord and neural tissue was also affected in the regenerating tails of wnt5a KO tadpoles. Our findings demonstrate that Wnt5a acts downstream of JunB and InhibinβA to maintain cell proliferation and that it also promotes differentiation in Xenopus tadpole tail regeneration.