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.
Highlights
Aminoglycosides can be ototoxic and induce caspasemediated apoptosis in hair cell (HC)
Previous studies have reported that Wnt/β-catenin inhibits the pro-apoptotic transcription factor Foxo[3] and protects against oxidative stress-induced apoptosis though downregulation of forkhead box O3 transcription factor (Foxo3).14,15,28 We investigated the Foxo[3] expression in neomycin-treated cochleae
HCs was associated with a decrease in oxidative stress. These results showed that antioxidant treatment successfully rescued the β-catenin deficiency-induced HC loss in Gfi1-Cre/β-cateninflox(exon2–6) mice after neomycin injury, and demonstrated that reactive oxygen species (ROS) accumulation was the Discussion The role of Wnt/β-catenin signaling in cochlear development and HC regeneration has been extensively studied in the mouse inner ear
Summary
Aminoglycosides can be ototoxic and induce caspasemediated apoptosis in HCs. During mammalian inner ear development, canonical Wnt signaling is critical for otocyst induction and directs the formation of the vestibular organs.[1,2]. Bim, which belong to the BCL-2 family members and are the downstream target gene of Foxo[3,18] have been reported to regulate the expression of stress-response proteins and to be involved in apoptosis in multiple organs.[19,20,21] Overactivation of Wnt signaling inhibits Foxo3-induced apoptosis through upregulation of serum and glucocorticoid-inducible kinase 1 (SGK1),[22] and overexpression of Wnt/β-catenin signaling inhibits Foxo[3] signaling in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced liver injury.[23] the protective role of Wnt/β-catenin signaling against neomycin-induced HC loss in the mouse inner ear has been unclear. We used loss-of-function and gain-of-function mouse models to investigate the role of Wnt/β-catenin signaling in protecting HCs against aminoglycoside-induced
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
