Harmonin Mutations Cause Mechanotransduction Defects in Cochlear Hair Cells

Nicolas Grillet; Wei Xiong; Anna Reynolds; Piotr Kazmierczak; Takashi Sato; Concepcion Lillo; Rachel A. Dumont; Edith Hintermann; Anna Sczaniecka; Martin Schwander; David Williams; Bechara Kachar; Peter G. Gillespie; Ulrich Müller

doi:10.1016/j.neuron.2009.04.006

Harmonin Mutations Cause Mechanotransduction Defects in Cochlear Hair Cells

Nicolas Grillet, Wei Xiong, Anna Reynolds, Piotr Kazmierczak, Takashi Sato, Concepcion Lillo, Rachel A. Dumont, Edith Hintermann, Anna Sczaniecka, Martin Schwander, David Williams, Bechara Kachar, Peter G. Gillespie, Ulrich Müller

Otolaryngology

Research output: Contribution to journal › Article › peer-review

134 Scopus citations

Abstract

In hair cells, mechanotransduction channels are gated by tip links, the extracellular filaments that consist of cadherin 23 (CDH23) and protocadherin 15 (PCDH15) and connect the stereocilia of each hair cell. However, which molecules mediate cadherin function at tip links is not known. Here we show that the PDZ-domain protein harmonin is a component of the upper tip-link density (UTLD), where CDH23 inserts into the stereociliary membrane. Harmonin domains that mediate interactions with CDH23 and F-actin control harmonin localization in stereocilia and are necessary for normal hearing. In mice expressing a mutant harmonin protein that prevents UTLD formation, the sensitivity of hair bundles to mechanical stimulation is reduced. We conclude that harmonin is a UTLD component and contributes to establishing the sensitivity of mechanotransduction channels to displacement.

Original language	English (US)
Pages (from-to)	375-387
Number of pages	13
Journal	Neuron
Volume	62
Issue number	3
DOIs	https://doi.org/10.1016/j.neuron.2009.04.006
State	Published - May 14 2009

Keywords

CELLBIO
HUMDISEASE
MOLNEURO

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2009.04.006

Cite this

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title = "Harmonin Mutations Cause Mechanotransduction Defects in Cochlear Hair Cells",

abstract = "In hair cells, mechanotransduction channels are gated by tip links, the extracellular filaments that consist of cadherin 23 (CDH23) and protocadherin 15 (PCDH15) and connect the stereocilia of each hair cell. However, which molecules mediate cadherin function at tip links is not known. Here we show that the PDZ-domain protein harmonin is a component of the upper tip-link density (UTLD), where CDH23 inserts into the stereociliary membrane. Harmonin domains that mediate interactions with CDH23 and F-actin control harmonin localization in stereocilia and are necessary for normal hearing. In mice expressing a mutant harmonin protein that prevents UTLD formation, the sensitivity of hair bundles to mechanical stimulation is reduced. We conclude that harmonin is a UTLD component and contributes to establishing the sensitivity of mechanotransduction channels to displacement.",

keywords = "CELLBIO, HUMDISEASE, MOLNEURO",

author = "Nicolas Grillet and Wei Xiong and Anna Reynolds and Piotr Kazmierczak and Takashi Sato and Concepcion Lillo and Dumont, {Rachel A.} and Edith Hintermann and Anna Sczaniecka and Martin Schwander and David Williams and Bechara Kachar and Gillespie, {Peter G.} and Ulrich M{\"u}ller",

note = "Funding Information: We thank Anthony Ricci for help with electrophysiology and for comments on the manuscript; C. Ramos, G. Martin, and S. Kupriyanov for assistance in generating mice; and K. Spencer, M. Wood, and T. Fassel for help with microscopy and EM. This work was funded by NIH grants DC005969, DC007704 (U.M.), EYE07042 (D.W.), and DC002368 (P.G.); the Skaggs Institute for Chemical Biology (U.M.); a Jules and Doris Stein RPB professorship (D.W.); a C.J. Martin fellowship (#148939) NHMRC (Australia) (A.R.); and a fellowship from the Bruce Ford and Anne Smith Bundy Foundation (A.R. and W.X). ",

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doi = "10.1016/j.neuron.2009.04.006",

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T1 - Harmonin Mutations Cause Mechanotransduction Defects in Cochlear Hair Cells

AU - Grillet, Nicolas

AU - Xiong, Wei

AU - Reynolds, Anna

AU - Kazmierczak, Piotr

AU - Sato, Takashi

AU - Lillo, Concepcion

AU - Dumont, Rachel A.

AU - Hintermann, Edith

AU - Sczaniecka, Anna

AU - Schwander, Martin

AU - Williams, David

AU - Kachar, Bechara

AU - Gillespie, Peter G.

AU - Müller, Ulrich

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PY - 2009/5/14

Y1 - 2009/5/14

N2 - In hair cells, mechanotransduction channels are gated by tip links, the extracellular filaments that consist of cadherin 23 (CDH23) and protocadherin 15 (PCDH15) and connect the stereocilia of each hair cell. However, which molecules mediate cadherin function at tip links is not known. Here we show that the PDZ-domain protein harmonin is a component of the upper tip-link density (UTLD), where CDH23 inserts into the stereociliary membrane. Harmonin domains that mediate interactions with CDH23 and F-actin control harmonin localization in stereocilia and are necessary for normal hearing. In mice expressing a mutant harmonin protein that prevents UTLD formation, the sensitivity of hair bundles to mechanical stimulation is reduced. We conclude that harmonin is a UTLD component and contributes to establishing the sensitivity of mechanotransduction channels to displacement.

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ER -

Harmonin Mutations Cause Mechanotransduction Defects in Cochlear Hair Cells

Abstract

Keywords

ASJC Scopus subject areas

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