Integration of Tmc1/2 into the mechanotransduction complex in zebrafish hair cells is regulated by Transmembrane O-methyltransferase (Tomt)
- Oregon Health and Science University, United States
- University of Sheffield, United Kingdom
- 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
Elisabeth M Busch-Nentwich
Peter G Barr-Gillespie
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
- 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
- Received: May 9, 2017
- Accepted: May 20, 2017
- Accepted Manuscript published: May 23, 2017 (version 1)
- 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.
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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
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