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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 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

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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 9

Tmc1Δ and Tmc2Δ hair cell uptake of gentamicin.

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Tmc1Δ and Tmc2Δ hair cell uptake of gentamicin.
   
(A) After a 48-hour...
(A) After a 48-hour incubation in culture medium with 1 mM gentamicin, wild-type utricular hair bundles were almost completely eliminated, while Tmc1Δ/ΔTmc2Δ/Δ utricular hair cells retained an intact hair bundle. Scale bar: 10 μm. (B) The mean density of intact hair bundles (±SD) within the central area of more than 6 utricular maculae of each genotype is shown for each genotype. Tmc1Δ/+Tmc2Δ/Δ and Tmc1Δ/ΔTmc2Δ/Δ utricular maculae showed no significant difference between cultures grown with gentamicin in comparison with control cultures grown without gentamicin. Tmc1+/+Tmc2Δ/Δ utricular hair cells showed intermediate sensitivity to gentamicin. One-way ANOVA results for differences from normal control values are indicated: *P < 0.05; ***P < 0.001; NS, P > 0.05. (C) After a 6-hour incubation in culture medium with 1 mM gentamicin, robust immunoreactivity for gentamicin was detected in wild-type utricular hair cells, whereas no immunoreactivity for gentamicin was detected in Tmc1Δ/ΔTmc2Δ/Δ hair cells. Red, anti–myosin VI antibodies; green, anti-gentamicin antibodies. Scale bar: 10 μm. (D) After a 6-hour incubation in 1 mM gentamicin, robust immunoreactivity for gentamicin was detected in wild-type IHCs and OHCs, whereas no immunoreactivity for gentamicin was detected in Tmc1Δ/ΔTmc2Δ/Δ hair cells. Red, anti–myosin VI antibodies; green, anti-gentamicin antibodies. Filled arrowheads, IHCs; open arrowheads, OHCs. Scale bar: 10 μm. See also Supplemental Figures 7 and 8.
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