After a peripheral nerve injury, the remaining Schwann cells undergo proliferation and adopt a migratory phenotype to prepare for the regeneration of nerves. Celsr2 has been reported to play an important role in the development and maintenance of the function of the nervous system. However, the role and mechanism of Celsr2 during peripheral nerve regeneration remain unknown. Here, we showed that after sciatic nerve injury, Celsr2 mRNA and protein were significantly increased in nerve tissues. In addition, silencing Celsr2 decreased the ki67-positve portion and the migration distance of Schwann cells in vivo. In vitro, the results of MTT and EdU staining, transwell and wound healing assays indicated that Celsr2 siRNA-transfected primary Schwann cells showed significant decrease in proliferation and migration compared to that seen in negative control (NC)-transfected cells. Furthermore, we found that Wnt/beta-catenin luciferase activity was reduced, as were the expression of beta-catenin in the nucleus and the mRNA levels of its downstream genes Cyclin D1 and MMP-7 in Celsr2 siRNA-transfected primary Schwann cells. Further investigations showed that silencing Celsr2 inhibited the phosphorylation of GSK3 beta. Moreover, specific activators of the Wnt/beta-catenin pathway, LiCl or mutant beta-catenin (S33Y), partially reversed the inhibitory effect of Celsr2 siRNA. Taken together, our data indicated that silencing Celsr2 inhibited Schwann cells migration and proliferation through the suppressing Wnt/beta-catenin pathway, providing a potential target for peripheral nerve regeneration. (C) 2020 The Authors. Published by Elsevier Inc.