Integration of Tmc1/2 into the mechanotransduction complex in zebrafish hair cells is regulated by Transmembrane O-methyltransferase (Tomt)

  1. Timothy Erickson
  2. Clive P Morgan
  3. Jennifer Olt
  4. Katherine Hardy
  5. Elisabeth M Busch-Nentwich
  6. Reo Maeda
  7. Rachel Clemens-Grisham
  8. Jocelyn F Krey
  9. Alex V Nechiporuk
  10. Peter G Barr-Gillespie
  11. Walter Marcotti
  12. Teresa Nicolson  Is a corresponding author
  1. Oregon Health and Science University, United States
  2. University of Sheffield, United Kingdom
  3. Wellcome Trust Sanger Institute, United Kingdom

Abstract

Transmembrane O-methyltransferase (TOMT / LRTOMT) is responsible for non-syndromic deafness DFNB63. However, the specific defects that lead to hearing loss have not been described. Using a zebrafish model of DFNB63, we show that the auditory and vestibular phenotypes are due to a lack of mechanotransduction (MET) in Tomt-deficient hair cells. GFP-tagged Tomt is enriched in the Golgi of hair cells, suggesting that Tomt might regulate the trafficking of other MET components to the hair bundle. We found that Tmc1/2 proteins are specifically excluded from the hair bundle in tomt mutants, whereas other MET complex proteins can still localize to the bundle. Furthermore, mouse TOMT and TMC1 can directly interact in HEK 293 cells, and this interaction is modulated by His183 in TOMT. Thus, we propose a model of MET complex assembly where Tomt and the Tmcs interact within the secretory pathway to traffic Tmc proteins to the hair bundle.

Article and author information

Author details

  1. Timothy Erickson

    Oregon Hearing Research Center and the Vollum Institute, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0910-2535
  2. Clive P Morgan

    Oregon Hearing Research Center and the Vollum Institute, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jennifer Olt

    Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Katherine Hardy

    Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Elisabeth M Busch-Nentwich

    Wellcome Trust Sanger Institute, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6450-744X
  6. Reo Maeda

    Oregon Hearing Research Center and the Vollum Institute, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Rachel Clemens-Grisham

    Oregon Hearing Research Center and the Vollum Institute, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Jocelyn F Krey

    Oregon Hearing Research Center and the Vollum Institute, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Alex V Nechiporuk

    Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Peter G Barr-Gillespie

    Oregon Hearing Research Center and the Vollum Institute, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9787-5860
  11. Walter Marcotti

    Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8770-7628
  12. Teresa Nicolson

    Oregon Hearing Research Center and the Vollum Institute, Oregon Health and Science University, Portland, United States
    For correspondence
    nicolson@ohsu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0873-1583

Funding

National Institutes of Health (R01DC013572)

  • Teresa Nicolson

National Institutes of Health (NIH R01 DC013531)

  • Teresa Nicolson

Wellcome Trust (102892)

  • Walter Marcotti

National Institutes of Health (R01DC002368)

  • Peter G Barr-Gillespie

National Institutes of Health (P30DC005983)

  • Peter G Barr-Gillespie

National Institutes of Health (R01DC002368)

  • Alex V Nechiporuk

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal research complied with guidelines stipulated by the Institutional Animal Care and Use Committed at Oregon Health and Science University (IP00000100). Electrophysiological recordings from zebrafish larvae were licensed by the Home Office under the Animals (Scientific Procedures) Act 1986 and were approved by the University of Sheffield Ethical Review Committee.

Copyright

© 2017, Erickson et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Timothy Erickson
  2. Clive P Morgan
  3. Jennifer Olt
  4. Katherine Hardy
  5. Elisabeth M Busch-Nentwich
  6. Reo Maeda
  7. Rachel Clemens-Grisham
  8. Jocelyn F Krey
  9. Alex V Nechiporuk
  10. Peter G Barr-Gillespie
  11. Walter Marcotti
  12. Teresa Nicolson
(2017)
Integration of Tmc1/2 into the mechanotransduction complex in zebrafish hair cells is regulated by Transmembrane O-methyltransferase (Tomt)
eLife 6:e28474.
https://doi.org/10.7554/eLife.28474

Share this article

https://doi.org/10.7554/eLife.28474

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