title: Cilia-Associated Genes Play Differing Roles in Aminoglycoside-Induced Hair Cell Death in Zebrafish.
abstract: Hair cells possess a single primary cilium, called the kinocilium, early in development. While the kinocilium is lost in auditory hair cells of most species it is maintained in vestibular hair cells. It has generally been believed that the primary role of the kinocilium and cilia-associated genes in hair cells is in the establishment of the polarity of actin-based stereocilia, the hair cell mechanotransduction apparatus. Through genetic screening and testing of candidate genes in zebrafish (Danio rerio) we have found that mutations in multiple cilia genes implicated in intraflagellar transport (dync2h1, wdr35, ift88, and traf3ip), and the ciliary transition zone (cc2d2a, mks1, and cep290) lead to resistance to aminoglycoside-induced hair cell death. These genes appear to have differing roles in hair cells, as mutations in intraflagellar transport genes, but not transition zone genes, lead to defects in kinocilia formation and processes dependent upon hair cell mechanotransduction activity. These mutants highlight a novel role of cilia-associated genes in hair cells, and provide powerful tools for further study.
authors.affiliation: Department of Biological Structure, University of Washington, Seattle, Washington 98195 Virginia Merrill Bloedel Hearing Research Center, University of Washington, Seattle, Washington 98195.
authors.forename: Tamara M
authors.initials: TM
authors.lastname: Stawicki
authors.affiliation: Department of Biological Structure, University of Washington, Seattle, Washington 98195.
authors.forename: Liana
authors.initials: L
authors.lastname: Hernandez
authors.affiliation: Virginia Merrill Bloedel Hearing Research Center, University of Washington, Seattle, Washington 98195 Department of Otolaryngology, Head and Neck Surgery, University of Washington, Seattle, Washington, 98195.
authors.forename: Robert
authors.initials: R
authors.lastname: Esterberg
authors.affiliation: Department of Biological Structure, University of Washington, Seattle, Washington 98195.
authors.forename: Tor
authors.initials: T
authors.lastname: Linbo
authors.affiliation: Department of Biological Structure, University of Washington, Seattle, Washington 98195 Virginia Merrill Bloedel Hearing Research Center, University of Washington, Seattle, Washington 98195 Department of Otolaryngology, Head and Neck Surgery, University of Washington, Seattle, Washington, 98195.
authors.forename: Kelly N
authors.initials: KN
authors.lastname: Owens
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109.
authors.forename: Arish N
authors.initials: AN
authors.lastname: Shah
authors.affiliation: Department of Biological Structure, University of Washington, Seattle, Washington 98195.
authors.forename: Nihal
authors.initials: N
authors.lastname: Thapa
authors.affiliation: Department of Biological Structure, University of Washington, Seattle, Washington 98195.
authors.forename: Brock
authors.initials: B
authors.lastname: Roberts
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109.
authors.forename: Cecilia B
authors.initials: CB
authors.lastname: Moens
authors.affiliation: Virginia Merrill Bloedel Hearing Research Center, University of Washington, Seattle, Washington 98195 Department of Otolaryngology, Head and Neck Surgery, University of Washington, Seattle, Washington, 98195.
authors.forename: Edwin W
authors.initials: EW
authors.lastname: Rubel
authors.affiliation: Department of Biological Structure, University of Washington, Seattle, Washington 98195 Virginia Merrill Bloedel Hearing Research Center, University of Washington, Seattle, Washington 98195 draible@uw.edu.
authors.forename: David W
authors.initials: DW
authors.lastname: Raible
mesh_terms: D000617:Aminoglycosides / Q000633:toxicity*; D000818:Animals; D016923:Cell Death; D002923:Cilia / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D056445:Cytoplasmic Dyneins / Q000235:genetics / Q000378:metabolism; D004361:Drug Tolerance / Q000235:genetics*; D015870:Gene Expression; D006198:Hair Cells, Auditory / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000617:Aminoglycosides; C569403:CC2D2A protein, zebrafish; C559615:CEP290 protein, zebrafish; D008869:Microtubule-Associated Proteins; D033921:Vesicular Transport Proteins; D029961:Zebrafish Proteins; D056445:Cytoplasmic Dyneins
keywords: aminoglycosides; cilia; hair cells; intraflagellar transport; transition zone