Mechanotransduction in mouse inner ear hair cells requires transmembrane channel–like genes
Yoshiyuki Kawashima, … , Jeffrey R. Holt, Andrew J. Griffith
Yoshiyuki Kawashima, … , Jeffrey R. Holt, Andrew J. Griffith
Published December 1, 2011; First published November 21, 2011
Citation Information: J Clin Invest. 2011;121(12):4796-4809. https://doi.org/10.1172/JCI60405.
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Research Article

Mechanotransduction in mouse inner ear hair cells requires transmembrane channel–like genes

Abstract

Inner ear hair cells convert the mechanical stimuli of sound, gravity, and head movement into electrical signals. This mechanotransduction process is initiated by opening of cation channels near the tips of hair cell stereocilia. Since the identity of these ion channels is unknown, and mutations in the gene encoding transmembrane channel–like 1 (TMC1) cause hearing loss without vestibular dysfunction in both mice and humans, we investigated the contribution of Tmc1 and the closely related Tmc2 to mechanotransduction in mice. We found that Tmc1 and Tmc2 were expressed in mouse vestibular and cochlear hair cells and that GFP-tagged TMC proteins localized near stereocilia tips. Tmc2 expression was transient in early postnatal mouse cochlear hair cells but persisted in vestibular hair cells. While mice with a targeted deletion of Tmc1 (Tmc1Δ mice) were deaf and those with a deletion of Tmc2 (Tmc2Δ mice) were phenotypically normal, Tmc1ΔTmc2Δ mice had profound vestibular dysfunction, deafness, and structurally normal hair cells that lacked all mechanotransduction activity. Expression of either exogenous TMC1 or TMC2 rescued mechanotransduction in Tmc1ΔTmc2Δ mutant hair cells. Our results indicate that TMC1 and TMC2 are necessary for hair cell mechanotransduction and may be integral components of the mechanotransduction complex. Our data also suggest that persistent TMC2 expression in vestibular hair cells may preserve vestibular function in humans with hearing loss caused by TMC1 mutations.

Authors

Yoshiyuki Kawashima, Gwenaëlle S.G. Géléoc, Kiyoto Kurima, Valentina Labay, Andrea Lelli, Yukako Asai, Tomoko Makishima, Doris K. Wu, Charles C. Della Santina, Jeffrey R. Holt, Andrew J. Griffith

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Figure 10

Localization of TMC2::AcGFP.

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Localization of TMC2::AcGFP. (A) Rat utricular hair cell transfected wit...
(A) Rat utricular hair cell transfected with MYO7A-Tmc2::AcGFP at P3 plus 1 day in vitro (P3+1DIV) and incubated for 48 hours. TMC2::AcGFP accumulates toward the tips of stereocilia. Scale bar: 5 μm. Gamma settings for red and green channels were adjusted equally throughout entire images using Adobe Photoshop CS5. (B) Rat saccular hair cell transfected with MYO7A-Tmc2::AcGFP at P3+1DIV and incubated for 48 hours. TMC2::AcGFP accumulates toward the tips of stereocilia. Scale bar: 5 μm. (C) Tmc1Δ/ΔTmc2Δ/Δ inner hair cells transfected with MYO7A-Tmc2::AcGFP at P0+1DIV and incubated for 72 hours. TMC2::AcGFP expression was detected on stereocilia. Gamma settings for red and green channels were adjusted equally throughout the entire image using Adobe Photoshop CS5. Scale bar: 5 μm. (D) Rat OHCs transfected with MYO7A-Tmc2::AcGFP at P0+1DIV and incubated for 72 hours. TMC2::AcGFP accumulates toward the tips of stereocilia. Scale bar: 5 μm. Gamma settings for red and green channels were adjusted equally throughout the entire image using Adobe Photoshop CS5. Cumulative totals of approximately 80 of 100 TMC2::AcGFP-positive hair cells each from cochleae, saccules, and utricles displayed green fluorescence at stereocilia tips. See also Supplemental Figure 9.