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PMID:22105175

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Citation

Kawashima, Y, Géléoc, GS, Kurima, K, Labay, V, Lelli, A, Asai, Y, Makishima, T, Wu, DK, Della Santina, CC, Holt, JR and Griffith, AJ (2011) Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes. J. Clin. Invest. 121:4796-809

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.

Links

PubMed PMC3223072 Online version:10.1172/JCI60405

Keywords

Animals; Cells, Cultured/drug effects; Cells, Cultured/metabolism; Deafness/genetics; Female; Fluorescent Dyes/metabolism; Genetic Complementation Test; Gentamicins/metabolism; Hair Cells, Auditory, Inner/physiology; Hair Cells, Auditory, Inner/ultrastructure; Hair Cells, Vestibular/physiology; Hair Cells, Vestibular/ultrastructure; Male; Mechanotransduction, Cellular/genetics; Mechanotransduction, Cellular/physiology; Membrane Proteins/deficiency; Membrane Proteins/genetics; Membrane Proteins/physiology; Mice; Mice, Inbred C57BL; Protein Isoforms/biosynthesis; Protein Isoforms/genetics; Protein Isoforms/physiology; Pyridinium Compounds/metabolism; Quaternary Ammonium Compounds/metabolism; RNA, Messenger/biosynthesis; Stereocilia/physiology; Stereocilia/ultrastructure

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:MYO6

located_in

GO:0048471: perinuclear region of cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0002374)

Seeded From UniProt

complete

MOUSE:TMC2

located_in

GO:0032426: stereocilium tip

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0002374)

Seeded From UniProt

complete

MOUSE:TMC2

acts_upstream_of_or_within

GO:0050910: detection of mechanical stimulus involved in sensory perception of sound

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2151016

P

Seeded From UniProt

complete

MOUSE:TMC2

acts_upstream_of_or_within

GO:0060005: vestibular reflex

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2151016

P

Seeded From UniProt

complete

MOUSE:TMC1

located_in

GO:0032426: stereocilium tip

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0002374)

Seeded From UniProt

complete

MOUSE:TMC1

acts_upstream_of_or_within

GO:0050910: detection of mechanical stimulus involved in sensory perception of sound

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5427097

P

Seeded From UniProt

complete

MOUSE:TMC1

acts_upstream_of_or_within

GO:0050910: detection of mechanical stimulus involved in sensory perception of sound

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2151017

P

Seeded From UniProt

complete

MOUSE:TMC1

acts_upstream_of_or_within

GO:0060117: auditory receptor cell development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5427097

P

Seeded From UniProt

complete

MOUSE:TMC1

acts_upstream_of_or_within

GO:0060005: vestibular reflex

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2151017

P

Seeded From UniProt

complete


See also

References

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