Abstract
Mutations in Myo7a cause hereditary deafness in mice and humans. We describe the effects of two mutations, Myo7a6J and Myo7a4626SB, on mechano-electrical transduction in cochlear hair cells. Both mutations result in two major functional abnormalities that would interfere with sound transduction. The hair bundles need to be displaced beyond their physiological operating range for mechanotransducer channels to open. Transducer currents also adapt more strongly than normal to excitatory stimuli. We conclude that myosin VIIA participates in anchoring and holding membrane-bound elements to the actin core of the stereocilium. Myosin VIIA is therefore required for the normal gating of transducer channels.
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References
Gibson, F. et al. A type VII myosin encoded by the mouse deafness gene shaker-1. Nature 374, 62–64 (1995).
Weil, D. et al. Defective myosin VIIA gene responsible for Usher syndrome type 1B. Nature 374, 60–61 (1995).
Liu, X. Z. et al. Mutations in the myosin VIIA gene cause non-syndromic recessive deafness. Nat. Genet. 16, 188–190 (1997).
Weil, D. et al. The autosomal recessive isolated deafness, DFNB2, and the Usher 1B syndrome are allelic defects of the myosin-VIIA gene. Nat. Genet. 16, 191–193 (1997).
Lord, E. M. & Gates, W. H. Shaker, a new mutation of the house mouse (Mus musculus). Am. Nat. 63, 435–442 (1929).
Hasson, T. et al. Unconventional myosins in inner-ear sensory epithelia. J. Cell Biol. 137, 1287–1307 (1997).
Self, T. et al. Shaker-1 mutations reveal roles for myosin VIIA in both development and function of cochlear hair cells. Development 125, 557–566 (1998).
Richardson, G. P. et al. Myosin VIIA is required for aminoglycoside accumulation in cochlear hair cells. J. Neurosci. 17, 9506–9519 (1997).
Gale, J. E., Marcotti, W., Kennedy, H. J., Kros, C. J. & Richardson, G. P. FM1-43 dye behave as a permeant blocker of the hair-cell's mechanotransducer channel. J. Neurosci. 21, 7013–7025 (2001).
Mburu, P. et al. Mutation analysis of the mouse myosin VIIA deafness gene. Genes Funct. 1, 191–203 (1997).
Richardson, G.P. et al. A missense mutation in myosin VIIA prevents aminoglycoside accumulation in early postnatal cochlea hair cells. NY Acad. Sci. 884, 110–124 (1999).
Eatock, R. A., Corey, D. P. & Hudspeth, A. J. Adaptation of mechanoelectrical transduction in hair cells of the bullfrog's sacculus. J. Neurosci. 7, 2821–2836 (1987).
Howard, J. & Hudspeth, A. J. Mechanical relaxation of the hair bundle mediates adaptation in mechanoelectrical transduction by the bullfrog's saccular hair cell. Proc. Natl. Acad. Sci. USA 84, 3064–3068 (1987).
Assad, J. A., Hacohen, N. & Corey, D. P. Voltage dependence of adaptation and active bundle movement in bullfrog saccular hair cells. Proc. Natl. Acad. Sci. USA 86, 2918–2922 (1989).
Crawford, A. C., Evans, M. G. & Fettiplace, R. Activation and adaptation of transducer currents in turtle hair cells. J. Physiol. (Lond.) 419, 405–434 (1989).
Kros, C. J., Rüsch, A. & Richardson, G. P. Mechano-electrical transducer currents in hair cells of the cultured neonatal mouse cochlea. Proc. R. Soc. Lond. B Biol. Sci. 249, 185–193 (1992).
Kros, C. J., Lennan, G. W. T. & Richardson, G. P. in Active Hearing (ed. Flock, A.) 113–125 (Elsevier Science, Oxford, 1995).
Géléoc, G. S. G., Lennan, G. W. T., Richardson, G. P. & Kros, C. J. A quantitative comparison of mechanoelectrical transduction in vestibular and auditory hair cells of neonatal mice. Proc. R. Soc. Lond. B Biol. Sci. 264, 611–621 (1997).
Yamoah, E. N. & Gillespie, P. G. Phosphate analogs block adaptation in hair cells by inhibiting adaptation-motor force production. Neuron 17, 523–533 (1996).
Wu, Y. C., Ricci, A. J. & Fettiplace, R. Two components of transducer adaptation in auditory hair cells. J. Neurophysiol. 82, 2171–2181 (1999).
Ohmori, H. Mechano-electrical transduction currents in isolated vestibular hair cells of the chick. J. Physiol. (Lond.) 359, 189–217 (1985).
Kroese, A. B. A., Das, A. & Hudspeth, A. J. Blockage of the transduction channels of hair cells in the bullfrog's sacculus by aminoglycoside antibiotics. Hear. Res. 37, 203–217 (1989).
Rhode, W. S. & Geisler, C. D. Model of the displacement between opposing points on the tectorial membrane and reticular lamina. J. Acoust. Soc. Am. 42, 185–190 (1967).
Ruggero, M. A., Rich, N. C., Recio, A., Narayan, S. S. & Robles, L. Basilar-membrane responses to tones at the base of the chinchilla cochlea. J. Acoust. Soc. Am. 101, 2151–2163 (1997).
Yamoah, E. N. et al. Plasma membrane Ca2+-ATPase extrudes Ca2+ from hair cell stereocilia. J. Neurosci. 18, 610–624 (1998).
Dumont, R. A. et al. Plasma membrane Ca2+-ATPase isoform 2a is the PMCA of hair bundles. J. Neurosci. 21, 5066–5078 (2001).
Küssel-Andermann, P. et al. Vezatin, a novel transmembrane protein, bridges myosin VIIA to the cadherin-caterins complex. EMBO J. 19, 6020–6029 (2000).
Mangeat, P., Roy, C. & Martin, M. ERM proteins in cell adhesion and membrane dynamics. Trends Cell Biol. 9, 187–192 (1999).
Verpy, E. et al. A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies usher syndrome type 1C. Nat. Genet. 26, 51–55 (2000).
Di Palma, F. et al. Mutations in Cdh23, encoding a new type of cadherin, cause stereocilia disorganization in waltzer, the mouse model for Usher syndrome type 1D. Nat. Genet. 27, 103–107 (2001).
Bolz, H. et al. Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D. Nat. Genet. 27, 108–112 (2001).
Hudspeth, A. J. & Gillespie, P. G. Pulling springs to tune transduction: adaptation by hair cells. Neuron 12, 1–9 (1994).
Assad, J. A. & Corey, D. P. An active motor model for adaptation by vertebrate hair cells. J. Neurosci. 12, 3291–3309 (1992).
van Netten, S. M. & Kros, C. J. Gating energies and forces of the mammalian hair cell transducer channel and related hair bundle mechanics. Proc. R. Soc. Lond. B Biol. Sci. 267, 1915–1923 (2000).
Denk, W., Keolian, R. M. & Webb, W. W. Mechanical response of frog saccular hair bundles to the aminoglycoside block of mechanoelectrical transduction. J. Neurophysiol. 68, 927–932 (1992).
Howard, J. & Hudspeth, A. J. Compliance of the hair bundle associated with gating of mechanoelectrical transduction channels in the bullfrog's saccular hair cell. Neuron 1, 189–199 (1988).
Shepherd, G. M. & Corey, D. P. The extent of adaptation in bullfrog saccular hair cells. J. Neurosci. 14, 6217–6229 (1994).
Gillespie, P. G. & Corey, D. P. Myosin and adaptation by hair cells. Neuron 19, 955–958 (1997).
Holt, J. R. & Corey, D. P. Two mechanisms for transducer adaptation in vertebrate hair cells. Proc. Natl. Acad. Sci. USA 97, 11730–11735 (2000).
Gillespie, P. G., Wagner, M. C. & Hudspeth, A. J. Identification of a 120 kd hair-bundle myosin located near stereociliary tips. Neuron 11, 581–594 (1993).
Garcia, J. A., Yee, A. G., Gillespie, P. G. & Corey, D. P. Localization of myosin-Iβ near both ends of tip links in frog saccular hair cells. J. Neurosci. 18, 8637–8647 (1998).
Self, T. et al. Role of myosin VI in the differentiation of cochlear hair cells. Dev. Biol. 214, 331–341 (1999).
Probst, F. J. et al. Correction of deafness in shaker-2 mice by an unconventional myosin in a BAC transgene. Science 280, 1444–1447 (1998).
Russell, I. J. & Richardson, G. P. The morphology and physiology of hair cells in organotypic cultures of the mouse cochlea. Hear. Res. 31, 9–24 (1987).
Marcotti, W. & Kros, C. J. Developmental expression of the potassium current IK,n contributes to maturation of mouse outer hair cells. J. Physiol. (Lond.) 520, 653–660 (1999).
Goodno, C. C. & Taylor, E. W. Inhibition of actomyosin ATPase by vanadate. Proc. Natl. Acad. Sci. USA 79, 21–25 (1982).
Barry, P. H. JPCalc, a software package for calculating liquid junction potential corrections in patch-clamp, intracellular, epithelial and bilayer measurements and for correcting junction potential measurements. J. Neurosci. Methods 51, 107–116 (1994).
Acknowledgements
This work was supported by the MRC, Defeating Deafness and the EC. We thank J. Fleming for help with genotyping. G. Richardson is supported by the Wellcome Trust.
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Kros, C., Marcotti, W., van Netten, S. et al. Reduced climbing and increased slipping adaptation in cochlear hair cells of mice with Myo7a mutations. Nat Neurosci 5, 41–47 (2002). https://doi.org/10.1038/nn784
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DOI: https://doi.org/10.1038/nn784
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