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 7

Rescue of mechanotransduction with Tmc1 or Tmc2.

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Rescue of mechanotransduction with Tmc1 or Tmc2. (A) Organotypic cul...
(A) Organotypic cultures of utricles harvested at P0–P3 from Tmc1Δ/ΔTmc2Δ/Δ mice were exposed to adenoviral vectors expressing Tmc1ex1 (n = 4 mice), Tmc1ex2 (n = 3 mice), Tmc2 (n = 5 mice), or Tmc1ex2-dn (n = 3 mice) and maintained in culture for 2–4 days. Scale bars apply to all current families. The envelope of the stimulus protocol is shown at the bottom left. (B) For each bar, the upper number indicates the number of cells with measurable mechanotransduction currents, while the lower number indicates total number of tested cells. Mean maximal currents are plotted from cells with measurable current (±SEM). (C) Organotypic cultures of cochleae were harvested from Tmc1Δ/ΔTmc2Δ/Δ mice at P0. Representative mechanotransduction current families for cochlear OHCs transfected with CMV promoter–driven Ad-Tmc1ex1 (n = 4 mice) or MYO7A promoter–driven Ad-Tmc2 (n = 11 mice). Ad-Tmc1ex1 or Ad-Tmc2 rescue mechanotransduction in Tmc1Δ/ΔTmc2Δ/Δ OHCs. Scale bars apply to both current families. The envelope of the stimulus protocol is shown at the bottom left. (D) Summary bar graph shows mean maximal mechanotransduction current amplitudes (±SEM) from 43 RFP-positive (transfected) OHCs. For each bar, the upper number indicates the number of cells with measurable mechanotransduction currents, while the lower number indicates total number of cells examined.