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.

Reviewing Editor

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

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.

Version history

  1. Received: May 9, 2017
  2. Accepted: May 20, 2017
  3. Accepted Manuscript published: May 23, 2017 (version 1)
  4. Version of Record published: June 7, 2017 (version 2)

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.

Metrics

  • 2,482
    Page views
  • 440
    Downloads
  • 42
    Citations

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

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. 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

Further reading

    1. Neuroscience
    2. Stem Cells and Regenerative Medicine
    Junjun Yao, Shaoxing Dai ... Tianqing Li
    Research Article

    While accumulated publications support the existence of neurogenesis in the adult human hippocampus, the homeostasis and developmental potentials of neural stem cells (NSCs) under different contexts remain unclear. Based on our generated single-nucleus atlas of the human hippocampus across neonatal, adult, aging, and injury, we dissected the molecular heterogeneity and transcriptional dynamics of human hippocampal NSCs under different contexts. We further identified new specific neurogenic lineage markers that overcome the lack of specificity found in some well-known markers. Based on developmental trajectory and molecular signatures, we found that a subset of NSCs exhibit quiescent properties after birth, and most NSCs become deep quiescence during aging. Furthermore, certain deep quiescent NSCs are reactivated following stroke injury. Together, our findings provide valuable insights into the development, aging, and reactivation of the human hippocampal NSCs, and help to explain why adult hippocampal neurogenesis is infrequently observed in humans.

    1. Developmental Biology
    2. Neuroscience
    Kristine B Walhovd, Stine K Krogsrud ... Didac Vidal-Pineiro
    Research Article

    Human fetal development has been associated with brain health at later stages. It is unknown whether growth in utero, as indexed by birth weight (BW), relates consistently to lifespan brain characteristics and changes, and to what extent these influences are of a genetic or environmental nature. Here we show remarkably stable and lifelong positive associations between BW and cortical surface area and volume across and within developmental, aging and lifespan longitudinal samples (N = 5794, 4–82 y of age, w/386 monozygotic twins, followed for up to 8.3 y w/12,088 brain MRIs). In contrast, no consistent effect of BW on brain changes was observed. Partly environmental effects were indicated by analysis of twin BW discordance. In conclusion, the influence of prenatal growth on cortical topography is stable and reliable through the lifespan. This early-life factor appears to influence the brain by association of brain reserve, rather than brain maintenance. Thus, fetal influences appear omnipresent in the spacetime of the human brain throughout the human lifespan. Optimizing fetal growth may increase brain reserve for life, also in aging.