The Murine Catecholamine Methyltransferase mTOMT is Essential for Mechanotransduction by Cochlear Hair Cells

  1. Christopher L Cunningham
  2. Zizhen Wu
  3. Aria Jafari
  4. Bo Zhao
  5. Kat Schrode
  6. Sarah Harkins-Perry
  7. Amanda Lauer
  8. Ulrich Mueller  Is a corresponding author
  1. Johns Hopkins University, United States
  2. UCSD, United States
  3. Indiana University School of Medicine, United States
  4. TSRI, United States

Abstract

Hair cells of the cochlea are mechanosensors for the perception of sound. Mutations in the LRTOMT gene, which encodes a protein with homology to the catecholamine methyltransferase COMT that is linked to schizophrenia, cause deafness. Here we show that Tomt/Comt2, the murine ortholog of LRTOMT, has an unexpected function in the regulation of mechanotransduction by hair cells. The role of mTOMT in hair cells is independent of mTOMT methyltransferase function and mCOMT cannot substitute for mTOMT function. Instead, mTOMT binds to putative components of the mechanotransduction channel in hair cells and is essential for the transport of some of these components into the mechanically sensitive stereocilia of hair cells. Our studies thus suggest functional diversification between mCOMT and mTOMT, where mTOMT is critical for the assembly of the mechanotransduction machinery of hair cells. Defects in this process are likely mechanistically linked to deafness caused by mutations in LRTOMT/Tomt.

Article and author information

Author details

  1. Christopher L Cunningham

    Neuroscience, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  2. Zizhen Wu

    Neuroscience, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  3. Aria Jafari

    Otolaryngology, UCSD, San Diego, United States
    Competing interests
    No competing interests declared.
  4. Bo Zhao

    Department of Otolaryngology Head & Neck Surgery, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    No competing interests declared.
  5. Kat Schrode

    Otolaryngology, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  6. Sarah Harkins-Perry

    Cell Biology, TSRI, San Diego, United States
    Competing interests
    No competing interests declared.
  7. Amanda Lauer

    Otolaryngology-HNS, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4184-7374
  8. Ulrich Mueller

    Neuroscience, Johns Hopkins University, Baltimore, United States
    For correspondence
    umuelle3@jhmi.edu
    Competing interests
    Ulrich Mueller, Ulrich Mueller is a founder of Decibel Therapeutics.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2736-6494

Funding

National Institute on Deafness and Other Communication Disorders (5965)

  • Ulrich Mueller

National Institute on Deafness and Other Communication Disorders (7704)

  • Ulrich Mueller

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

Ethics

Animal experimentation: All animal experiments were approved by the Institutional Animal Care and Use Committee at Johns Hopkins University School of Medicine (#M016M271).

Reviewing Editor

  1. David D Ginty, Howard Hughes Medical Institute, Harvard Medical School, United States

Publication history

  1. Received: December 19, 2016
  2. Accepted: May 14, 2017
  3. Accepted Manuscript published: May 15, 2017 (version 1)
  4. Version of Record published: June 7, 2017 (version 2)
  5. Version of Record updated: November 8, 2017 (version 3)

Copyright

© 2017, Cunningham 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. Christopher L Cunningham
  2. Zizhen Wu
  3. Aria Jafari
  4. Bo Zhao
  5. Kat Schrode
  6. Sarah Harkins-Perry
  7. Amanda Lauer
  8. Ulrich Mueller
(2017)
The Murine Catecholamine Methyltransferase mTOMT is Essential for Mechanotransduction by Cochlear Hair Cells
eLife 6:e24318.
https://doi.org/10.7554/eLife.24318

Further reading

    1. Developmental Biology
    2. Neuroscience
    Matthew P Bostock, Anadika R Prasad ... Vilaiwan M Fernandes
    Research Article Updated

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