Wnt activation protects against neomycin-induced hair cell damage in the mouse cochlea

Recent studies have reported the role of Wnt/beta-catenin signaling in hair cell (HC) development, regeneration, and differentiation in the mouse cochlea; however, the role of Wnt/beta-catenin signaling in HC protection remains unknown. In this study, we took advantage of transgenic mice to specifically knockout or overactivate the canonical Wnt signaling mediator beta-catenin in HCs, which allowed us to investigate the role of Wnt/beta-catenin signaling in protecting HCs against neomycin-induced damage. We first showed that loss of beta-catenin in HCs made them more vulnerable to neomycin-induced injury, while constitutive activation of beta-catenin in HCs reduced HC loss both in vivo and in vitro. We then showed that loss of beta-catenin in HCs increased caspase-mediated apoptosis induced by neomycin injury, while beta-catenin overexpression inhibited caspase-mediated apoptosis. Finally, we demonstrated that loss of beta-catenin in HCs led to increased expression of forkhead box O3 transcription factor (Foxo3) and Bim along with decreased expression of antioxidant enzymes; thus, there were increased levels of reactive oxygen species (ROS) after neomycin treatment that might be responsible for the increased aminoglycoside sensitivity of HCs. In contrast, beta-catenin overexpression reduced Foxo3 and Bim expression and ROS levels, suggesting that beta-catenin is protective against neomycin-induced HC loss. Our findings demonstrate that Wnt/beta-catenin signaling has an important role in protecting HCs against neomycin-induced HC loss and thus might be a new therapeutic target for the prevention of HC death.