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Reduced climbing and increased slipping adaptation in cochlear hair cells of mice with Myo7a mutations

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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Figure 1: Effects of myosin VIIA mutations on hair bundle structure.
Figure 2: Mechano-electrical transduction in a heterozygous control OHC (+/6J, P7).
Figure 3: Mechano-electrical transduction in homozygous mutant OHCs.
Figure 4: Effects of vanadate and dihydrostreptomycin (DHS) on transducer currents.
Figure 5: Models of the functional consequences of a lack of myosin VIIA motors.

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References

  1. Gibson, F. et al. A type VII myosin encoded by the mouse deafness gene shaker-1. Nature 374, 62–64 (1995).

    Article  CAS  Google Scholar 

  2. Weil, D. et al. Defective myosin VIIA gene responsible for Usher syndrome type 1B. Nature 374, 60–61 (1995).

    Article  CAS  Google Scholar 

  3. Liu, X. Z. et al. Mutations in the myosin VIIA gene cause non-syndromic recessive deafness. Nat. Genet. 16, 188–190 (1997).

    Article  CAS  Google Scholar 

  4. 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).

    Article  CAS  Google Scholar 

  5. Lord, E. M. & Gates, W. H. Shaker, a new mutation of the house mouse (Mus musculus). Am. Nat. 63, 435–442 (1929).

    Article  Google Scholar 

  6. Hasson, T. et al. Unconventional myosins in inner-ear sensory epithelia. J. Cell Biol. 137, 1287–1307 (1997).

    Article  CAS  Google Scholar 

  7. 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).

    CAS  PubMed  Google Scholar 

  8. Richardson, G. P. et al. Myosin VIIA is required for aminoglycoside accumulation in cochlear hair cells. J. Neurosci. 17, 9506–9519 (1997).

    Article  CAS  Google Scholar 

  9. 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).

    Article  CAS  Google Scholar 

  10. Mburu, P. et al. Mutation analysis of the mouse myosin VIIA deafness gene. Genes Funct. 1, 191–203 (1997).

    Article  CAS  Google Scholar 

  11. 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).

    CAS  Google Scholar 

  12. 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).

    Article  CAS  Google Scholar 

  13. 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).

    Article  CAS  Google Scholar 

  14. 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).

    Article  CAS  Google Scholar 

  15. 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).

    Article  CAS  Google Scholar 

  16. 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).

    Article  CAS  Google Scholar 

  17. Kros, C. J., Lennan, G. W. T. & Richardson, G. P. in Active Hearing (ed. Flock, A.) 113–125 (Elsevier Science, Oxford, 1995).

    Google Scholar 

  18. 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).

    Article  Google Scholar 

  19. Yamoah, E. N. & Gillespie, P. G. Phosphate analogs block adaptation in hair cells by inhibiting adaptation-motor force production. Neuron 17, 523–533 (1996).

    Article  CAS  Google Scholar 

  20. Wu, Y. C., Ricci, A. J. & Fettiplace, R. Two components of transducer adaptation in auditory hair cells. J. Neurophysiol. 82, 2171–2181 (1999).

    Article  CAS  Google Scholar 

  21. Ohmori, H. Mechano-electrical transduction currents in isolated vestibular hair cells of the chick. J. Physiol. (Lond.) 359, 189–217 (1985).

    Article  CAS  Google Scholar 

  22. 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).

    Article  CAS  Google Scholar 

  23. 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).

    Article  CAS  Google Scholar 

  24. 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).

    Article  CAS  Google Scholar 

  25. Yamoah, E. N. et al. Plasma membrane Ca2+-ATPase extrudes Ca2+ from hair cell stereocilia. J. Neurosci. 18, 610–624 (1998).

    Article  CAS  Google Scholar 

  26. Dumont, R. A. et al. Plasma membrane Ca2+-ATPase isoform 2a is the PMCA of hair bundles. J. Neurosci. 21, 5066–5078 (2001).

    Article  CAS  Google Scholar 

  27. Küssel-Andermann, P. et al. Vezatin, a novel transmembrane protein, bridges myosin VIIA to the cadherin-caterins complex. EMBO J. 19, 6020–6029 (2000).

    Article  Google Scholar 

  28. Mangeat, P., Roy, C. & Martin, M. ERM proteins in cell adhesion and membrane dynamics. Trends Cell Biol. 9, 187–192 (1999).

    Article  CAS  Google Scholar 

  29. 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).

    Article  CAS  Google Scholar 

  30. 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).

    Article  CAS  Google Scholar 

  31. 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).

    Article  CAS  Google Scholar 

  32. Hudspeth, A. J. & Gillespie, P. G. Pulling springs to tune transduction: adaptation by hair cells. Neuron 12, 1–9 (1994).

    Article  CAS  Google Scholar 

  33. Assad, J. A. & Corey, D. P. An active motor model for adaptation by vertebrate hair cells. J. Neurosci. 12, 3291–3309 (1992).

    Article  CAS  Google Scholar 

  34. 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).

    Article  CAS  Google Scholar 

  35. 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).

    Article  CAS  Google Scholar 

  36. 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).

    Article  CAS  Google Scholar 

  37. Shepherd, G. M. & Corey, D. P. The extent of adaptation in bullfrog saccular hair cells. J. Neurosci. 14, 6217–6229 (1994).

    Article  CAS  Google Scholar 

  38. Gillespie, P. G. & Corey, D. P. Myosin and adaptation by hair cells. Neuron 19, 955–958 (1997).

    Article  CAS  Google Scholar 

  39. Holt, J. R. & Corey, D. P. Two mechanisms for transducer adaptation in vertebrate hair cells. Proc. Natl. Acad. Sci. USA 97, 11730–11735 (2000).

    Article  CAS  Google Scholar 

  40. 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).

    Article  CAS  Google Scholar 

  41. 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).

    Article  CAS  Google Scholar 

  42. Self, T. et al. Role of myosin VI in the differentiation of cochlear hair cells. Dev. Biol. 214, 331–341 (1999).

    Article  CAS  Google Scholar 

  43. 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).

    Article  CAS  Google Scholar 

  44. 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).

    Article  CAS  Google Scholar 

  45. 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).

    Article  CAS  Google Scholar 

  46. Goodno, C. C. & Taylor, E. W. Inhibition of actomyosin ATPase by vanadate. Proc. Natl. Acad. Sci. USA 79, 21–25 (1982).

    Article  CAS  Google Scholar 

  47. 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).

    Article  CAS  Google Scholar 

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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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Correspondence to C. J. Kros.

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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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