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

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 2

Tmc1Δ and Tmc2Δ mice.

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Tmc1Δ and Tmc2Δ mice. (A) Generation of Tmc1Δ mice. Schematic diagr...
(A) Generation of Tmc1Δ mice. Schematic diagram of the Tmc1 genomic locus, targeting vector, and targeted locus before and after Cre-mediated excision of PGK-Neo. 5′ and 3′ hybridization probes and restriction digestion sites for Southern blot analysis are indicated. TK encodes thymidine kinase. (B) Generation of Tmc2Δ mice. (C) Southern blot analyses of Tmc1 targeting. Genomic DNA was digested with NcoI for 5′ probe hybridization and EcoRV for 3′ probe hybridization. (D) Southern blot analyses of Tmc2 targeting. Genomic DNA was digested with NheI and KpnI for 5′ probe hybridization and BglI and HindIII for 3′ probe hybridization. The sizes of the Tmc1Δ and Tmc2Δ hybridizing bands confirmed proper integration of the targeting constructs. See also Supplemental Figure 2.