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Integration of Tmc1/2 into the mechanotransduction complex in zebrafish hair cells is regulated by Transmembrane O-methyltransferase (Tomt).

Published version
Peer-reviewed

Type

Article

Change log

Authors

Morgan, Clive P 
Olt, Jennifer 
Hardy, Katherine 
Busch-Nentwich, Elisabeth  ORCID logo  https://orcid.org/0000-0001-6450-744X

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.

Description

Keywords

deafness, hair cells, mechanotransduction, neuroscience, tomt, transmembrane channel-like proteins, zebrafish, Animals, Disease Models, Animal, Hair Cells, Auditory, Hearing Loss, Sensorineural, Mechanotransduction, Cellular, Membrane Proteins, Methyltransferases, Mutation, Zebrafish, Zebrafish Proteins

Journal Title

Elife

Conference Name

Journal ISSN

2050-084X
2050-084X

Volume Title

6

Publisher

eLife Sciences Publications, Ltd