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.
authors.affiliation: Department of Cell Biology, Institute for Childhood and Neglected Disease, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Grillet
authors.forename: Wei
authors.initials: W
authors.lastname: Xiong
authors.forename: Anna
authors.initials: A
authors.lastname: Reynolds
authors.forename: Piotr
authors.initials: P
authors.lastname: Kazmierczak
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.forename: Concepcion
authors.initials: C
authors.lastname: Lillo
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Dumont
authors.forename: Edith
authors.initials: E
authors.lastname: Hintermann
authors.forename: Anna
authors.initials: A
authors.lastname: Sczaniecka
authors.forename: Martin
authors.initials: M
authors.lastname: Schwander
authors.forename: David
authors.initials: D
authors.lastname: Williams
authors.forename: Bechara
authors.initials: B
authors.lastname: Kachar
authors.forename: Peter G
authors.initials: PG
authors.lastname: Gillespie
authors.forename: Ulrich
authors.initials: U
authors.lastname: Müller
mesh_terms: D000818:Animals; D015820:Cadherins / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins; D022081:Cell Surface Extensions / Q000502:physiology*; D003598:Cytoskeletal Proteins; D006199:Hair Cells, Auditory, Inner / Q000502:physiology*; D006309:Hearing / Q000502:physiology*; D015640:Ion Channel Gating / Q000502:physiology; D040542:Mechanotransduction, Cellular / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D054731:PDZ Domains; D004856:Postural Balance / Q000502:physiology
chemical_list: D015820:Cadherins; D002352:Carrier Proteins; C499091:Cdh23 protein, mouse; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; C492262:Ush1c protein, mouse