Integration of Tmc1/2 into the mechanotransduction complex in zebrafish hair cells is regulated by Transmembrane O-methyltransferase (Tomt)
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 mechanotransd...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2017-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/28474 |
| _version_ | 1811181405654220800 |
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| author | Timothy Erickson Clive P Morgan Jennifer Olt Katherine Hardy Elisabeth Busch-Nentwich Reo Maeda Rachel Clemens Jocelyn F Krey Alex Nechiporuk Peter G Barr-Gillespie Walter Marcotti Teresa Nicolson |
| author_facet | Timothy Erickson Clive P Morgan Jennifer Olt Katherine Hardy Elisabeth Busch-Nentwich Reo Maeda Rachel Clemens Jocelyn F Krey Alex Nechiporuk Peter G Barr-Gillespie Walter Marcotti Teresa Nicolson |
| author_sort | Timothy Erickson |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T09:17:13Z |
| format | Article |
| id | doaj.art-8c67b3aa4fc342c1bcf127fb9e97b312 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:17:13Z |
| publishDate | 2017-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-8c67b3aa4fc342c1bcf127fb9e97b3122022-12-22T04:32:18ZengeLife Sciences Publications LtdeLife2050-084X2017-05-01610.7554/eLife.28474Integration of Tmc1/2 into the mechanotransduction complex in zebrafish hair cells is regulated by Transmembrane O-methyltransferase (Tomt)Timothy Erickson0https://orcid.org/0000-0002-0910-2535Clive P Morgan1Jennifer Olt2Katherine Hardy3Elisabeth Busch-Nentwich4https://orcid.org/0000-0001-6450-744XReo Maeda5Rachel Clemens6Jocelyn F Krey7Alex Nechiporuk8Peter G Barr-Gillespie9https://orcid.org/0000-0002-9787-5860Walter Marcotti10https://orcid.org/0000-0002-8770-7628Teresa Nicolson11https://orcid.org/0000-0002-0873-1583Oregon Hearing Research Center and the Vollum Institute, Oregon Health and Science University, Portland, United StatesOregon Hearing Research Center and the Vollum Institute, Oregon Health and Science University, Portland, United StatesDepartment of Biomedical Science, University of Sheffield, Sheffield, United StatesDepartment of Biomedical Science, University of Sheffield, Sheffield, United StatesWellcome Trust Sanger Institute, Cambridge, United KingdomOregon Hearing Research Center and the Vollum Institute, Oregon Health and Science University, Portland, United StatesOregon Hearing Research Center and the Vollum Institute, Oregon Health and Science University, Portland, United StatesOregon Hearing Research Center and the Vollum Institute, Oregon Health and Science University, Portland, United StatesDepartment of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, United StatesOregon Hearing Research Center and the Vollum Institute, Oregon Health and Science University, Portland, United StatesDepartment of Biomedical Science, University of Sheffield, Sheffield, United StatesOregon Hearing Research Center and the Vollum Institute, Oregon Health and Science University, Portland, United StatesTransmembrane 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.https://elifesciences.org/articles/28474hair cellsmechanotransductiontransmembrane channel-like proteinstomtdeafnesszebrafish |
| spellingShingle | Timothy Erickson Clive P Morgan Jennifer Olt Katherine Hardy Elisabeth Busch-Nentwich Reo Maeda Rachel Clemens Jocelyn F Krey Alex Nechiporuk Peter G Barr-Gillespie Walter Marcotti Teresa Nicolson Integration of Tmc1/2 into the mechanotransduction complex in zebrafish hair cells is regulated by Transmembrane O-methyltransferase (Tomt) eLife hair cells mechanotransduction transmembrane channel-like proteins tomt deafness zebrafish |
| title | Integration of Tmc1/2 into the mechanotransduction complex in zebrafish hair cells is regulated by Transmembrane O-methyltransferase (Tomt) |
| title_full | Integration of Tmc1/2 into the mechanotransduction complex in zebrafish hair cells is regulated by Transmembrane O-methyltransferase (Tomt) |
| title_fullStr | Integration of Tmc1/2 into the mechanotransduction complex in zebrafish hair cells is regulated by Transmembrane O-methyltransferase (Tomt) |
| title_full_unstemmed | Integration of Tmc1/2 into the mechanotransduction complex in zebrafish hair cells is regulated by Transmembrane O-methyltransferase (Tomt) |
| title_short | Integration of Tmc1/2 into the mechanotransduction complex in zebrafish hair cells is regulated by Transmembrane O-methyltransferase (Tomt) |
| title_sort | integration of tmc1 2 into the mechanotransduction complex in zebrafish hair cells is regulated by transmembrane o methyltransferase tomt |
| topic | hair cells mechanotransduction transmembrane channel-like proteins tomt deafness zebrafish |
| url | https://elifesciences.org/articles/28474 |
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