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.
View: Text | PDF
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

×

Figure 6

Tmc1Δ and Tmc2Δ cochlear hair cell mechanotransduction currents.

Options: View larger image (or click on image) Download as PowerPoint
Tmc1Δ and Tmc2Δ cochlear hair cell mechanotransduction currents. (A...
(A) Representative mechanotransduction current families recorded from OHCs harvested at P5–P7 from the apical cochlea of mice of the indicated Tmc1;Tmc2 genotypes. Hair bundles were deflected for 90-ms steps that ranged from 200 nm to 750 nm in 50-nm increments while cells were held at a physiologically relevant holding potential (–64 mV). Some traces have been removed for clarity. The envelope of the stimulus protocol is shown at the bottom right. Tmc1Δ/ΔTmc2Δ/Δ OHCs lack mechanotransduction currents entirely. Scale bars apply to all current families. (B) Summary bar graph of mean maximal mechanotransduction current amplitudes (±SEM) from 100 apical OHCs. For each bar, the upper number indicates the number of mice examined, and the lower number indicates the total number of hair cells examined. Tmc1Δ/ΔTmc2+/+ and Tmc1Δ/ΔTmc2Δ/+ hair cells had intermediate current amplitudes. *P < 0.001, 1-way ANOVA, relative to wild-type values. (C) Representative transduction currents recorded from OHCs excised at P2–P4 from the basal end of the cochlea from mice of the indicated genotypes. The stimulus protocol and scale bars in A apply. (D) Summary bar graph of maximal mechanotransduction current amplitudes (±SEM) from 45 basal OHCs. Upper numbers indicate the numbers of mice examined, and lower numbers indicate the total numbers of cells examined. *P < 0.001, 1-way ANOVA, relative to wild-type values. See also Supplemental Figure 5.