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

Timothy Erickson, Clive P. Morgan, Jennifer Olt, Katherine Hardy, Elisabeth Busch-Nentwich, Reo Maeda, Rachel Clemens, Jocelyn F. Krey, Alex Nechiporuk, Peter Barr-Gillespie, Walter Marcotti, Teresa Nicolson

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere28474
JournaleLife
Volume6
DOIs
StatePublished - May 23 2017

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Methyltransferases
Zebrafish
Cells
Proteins
HEK293 Cells
Secretory Pathway
Audition
Deafness
Hearing Loss
Cell Communication
Phenotype
Defects
Autosomal Recessive 63 Deafness

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Integration of Tmc1/2 into the mechanotransduction complex in zebrafish hair cells is regulated by transmembrane o-methyltransferase (Tomt). / Erickson, Timothy; Morgan, Clive P.; Olt, Jennifer; Hardy, Katherine; Busch-Nentwich, Elisabeth; Maeda, Reo; Clemens, Rachel; Krey, Jocelyn F.; Nechiporuk, Alex; Barr-Gillespie, Peter; Marcotti, Walter; Nicolson, Teresa.

In: eLife, Vol. 6, e28474, 23.05.2017.

Research output: Contribution to journalArticle

Erickson, Timothy ; Morgan, Clive P. ; Olt, Jennifer ; Hardy, Katherine ; Busch-Nentwich, Elisabeth ; Maeda, Reo ; Clemens, Rachel ; Krey, Jocelyn F. ; Nechiporuk, Alex ; Barr-Gillespie, Peter ; Marcotti, Walter ; Nicolson, Teresa. / Integration of Tmc1/2 into the mechanotransduction complex in zebrafish hair cells is regulated by transmembrane o-methyltransferase (Tomt). In: eLife. 2017 ; Vol. 6.
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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.",
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AU - Erickson, Timothy

AU - Morgan, Clive P.

AU - Olt, Jennifer

AU - Hardy, Katherine

AU - Busch-Nentwich, Elisabeth

AU - Maeda, Reo

AU - Clemens, Rachel

AU - Krey, Jocelyn F.

AU - Nechiporuk, Alex

AU - Barr-Gillespie, Peter

AU - Marcotti, Walter

AU - Nicolson, Teresa

PY - 2017/5/23

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AB - 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.

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