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.

Reviewing Editor

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

Ethics

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

Version 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.

Metrics

  • 2,170
    Page views
  • 436
    Downloads
  • 19
    Citations

Article citation count generated by polling the highest count across the following sources: PubMed Central, Crossref, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.24318

Further reading

    1. Neuroscience
    Harry Clark, Matthew F Nolan
    Research Article

    Grid firing fields have been proposed as a neural substrate for spatial localisation in general or for path integration in particular. To distinguish these possibilities, we investigate firing of grid and non-grid cells in the mouse medial entorhinal cortex during a location memory task. We find that grid firing can either be anchored to the task environment, or can encode distance travelled independently of the task reference frame. Anchoring varied between and within sessions, while spatial firing of non-grid cells was either coherent with the grid population, or was stably anchored to the task environment. We took advantage of the variability in task-anchoring to evaluate whether and when encoding of location by grid cells might contribute to behaviour. We find that when reward location is indicated by a visual cue, performance is similar regardless of whether grid cells are task-anchored or not, arguing against a role for grid representations when location cues are available. By contrast, in the absence of the visual cue, performance was enhanced when grid cells were anchored to the task environment. Our results suggest that anchoring of grid cells to task reference frames selectively enhances performance when path integration is required.