title: Wnt activation protects against neomycin-induced hair cell damage in the mouse cochlea.
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.
authors.affiliation: Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, PR China.|Institutes of Biomedical Sciences, Fudan University, Shanghai, PR China.
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.affiliation: Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, PR China.|Laboratory Center, Affiliated Eye and ENT Hospital of Fudan University, Shanghai, PR China.|Key Laboratory of Hearing Medicine of National Health and Family Planning Commission, Shanghai, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, China.|Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.
authors.forename: J
authors.initials: J
authors.lastname: Qi
authors.affiliation: Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, PR China.|Laboratory Center, Affiliated Eye and ENT Hospital of Fudan University, Shanghai, PR China.|Key Laboratory of Hearing Medicine of National Health and Family Planning Commission, Shanghai, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, PR China.|Laboratory Center, Affiliated Eye and ENT Hospital of Fudan University, Shanghai, PR China.|Key Laboratory of Hearing Medicine of National Health and Family Planning Commission, Shanghai, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: He
authors.affiliation: Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, PR China.|Key Laboratory of Hearing Medicine of National Health and Family Planning Commission, Shanghai, PR China.
authors.forename: W
authors.initials: W
authors.lastname: Ni
authors.affiliation: Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, PR China.|Laboratory Center, Affiliated Eye and ENT Hospital of Fudan University, Shanghai, PR China.|Key Laboratory of Hearing Medicine of National Health and Family Planning Commission, Shanghai, PR China.
authors.forename: W
authors.identifier: http://orcid.org/0000-0002-3394-2278
authors.initials: W
authors.lastname: Li
authors.affiliation: Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, China.|Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.
authors.forename: S
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, PR China.|Laboratory Center, Affiliated Eye and ENT Hospital of Fudan University, Shanghai, PR China.|Key Laboratory of Hearing Medicine of National Health and Family Planning Commission, Shanghai, PR China.
authors.forename: S
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: M M
authors.initials: MM
authors.lastname: Taketo
authors.affiliation: Institutes of Biomedical Sciences, Fudan University, Shanghai, PR China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, China.|Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.
authors.forename: R
authors.initials: R
authors.lastname: Chai
authors.affiliation: Otorhinolaryngology Department of Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, PR China.|Institutes of Biomedical Sciences, Fudan University, Shanghai, PR China.|Key Laboratory of Hearing Medicine of National Health and Family Planning Commission, Shanghai, PR China.
authors.forename: H
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D016923:Cell Death; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006198:Hair Cells, Auditory / Q000378:metabolism* / Q000473:pathology; D034381:Hearing Loss / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009355:Neomycin / Q000009:adverse effects* / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects* / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D051176:beta Catenin; D009355:Neomycin