title: 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 (Tmc1(Δ) mice) were deaf and those with a deletion of Tmc2 (Tmc2(Δ) mice) were phenotypically normal, Tmc1(Δ)Tmc2(Δ) 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 Tmc1(Δ)Tmc2(Δ) 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: Molecular Biology and Genetics Section, National Institute on Deafness and Other Communication Disorders, NIH, Rockville, Maryland 20850-3320, USA.
authors: Yoshiyuki
authors: Y
authors: Kawashima
authors: Gwenaëlle S G
authors: GS
authors: Géléoc
authors: Kiyoto
authors: K
authors: Kurima
authors: Valentina
authors: V
authors: Labay
authors: Andrea
authors: A
authors: Lelli
authors: Yukako
authors: Y
authors: Asai
authors: Tomoko
authors: T
authors: Makishima
authors: Doris K
authors: DK
authors: Wu
authors: Charles C
authors: CC
authors: Della Santina
authors: Jeffrey R
authors: JR
authors: Holt
authors: Andrew J
authors: AJ
authors: Griffith
mesh_terms: D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D003638:Deafness / Q000235:genetics*; D005260:Female; D005456:Fluorescent Dyes / Q000378:metabolism; D005816:Genetic Complementation Test; D005839:Gentamicins / Q000378:metabolism; D006199:Hair Cells, Auditory, Inner / Q000502:physiology* / Q000648:ultrastructure; D018069:Hair Cells, Vestibular / Q000502:physiology* / Q000648:ultrastructure; D008297:Male; D040542:Mechanotransduction, Cellular / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D011726:Pyridinium Compounds / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D059547:Stereocilia / Q000502:physiology / Q000648:ultrastructure
chemical_list: C073804:FM1 43; D005456:Fluorescent Dyes; D005839:Gentamicins; D008565:Membrane Proteins; D020033:Protein Isoforms; D011726:Pyridinium Compounds; D000644:Quaternary Ammonium Compounds; D012333:RNA, Messenger; C514628:TMC1 protein, mouse