1. Wnt activation protects against neomycin-induced hair cell damage in the mouse cochlea
- Author
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Luman Wang, Makoto Mark Taketo, Shu-Na Sun, Y Chen, Yiyin Zhang, Shasha Zhang, Yingzi He, Lijuan Liu, Renjie Chai, Wenkai Ni, Hong-Fu Li, J Qi, and Weiliang Li
- Subjects
0301 basic medicine ,Genetically modified mouse ,Programmed cell death ,Cancer Research ,Beta-catenin ,Immunology ,Mice, Transgenic ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Mice ,0302 clinical medicine ,Proto-Oncogene Proteins ,Hair Cells, Auditory ,medicine ,Animals ,Hearing Loss ,Transcription factor ,Wnt Signaling Pathway ,beta Catenin ,biology ,Bcl-2-Like Protein 11 ,Cell Death ,Forkhead Box Protein O3 ,Wnt signaling pathway ,Membrane Proteins ,Forkhead Transcription Factors ,Neomycin ,Cell Biology ,Cell biology ,030104 developmental biology ,Apoptosis ,biology.protein ,FOXO3 ,Original Article ,sense organs ,Apoptosis Regulatory Proteins ,Reactive Oxygen Species ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Recent studies have reported the role of Wnt/β-catenin signaling in hair cell (HC) development, regeneration, and differentiation in the mouse cochlea; however, the role of Wnt/β-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 β-catenin in HCs, which allowed us to investigate the role of Wnt/β-catenin signaling in protecting HCs against neomycin-induced damage. We first showed that loss of β-catenin in HCs made them more vulnerable to neomycin-induced injury, while constitutive activation of β-catenin in HCs reduced HC loss both in vivo and in vitro. We then showed that loss of β-catenin in HCs increased caspase-mediated apoptosis induced by neomycin injury, while β-catenin overexpression inhibited caspase-mediated apoptosis. Finally, we demonstrated that loss of β-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, β-catenin overexpression reduced Foxo3 and Bim expression and ROS levels, suggesting that β-catenin is protective against neomycin-induced HC loss. Our findings demonstrate that Wnt/β-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.
- Published
- 2016