title: Inactivation of NADPH oxidase organizer 1 results in severe imbalance.
abstract: Otoconia are biominerals of the vestibular system that are indispensable for the perception of gravity. Despite their importance, the process of otoconia genesis is largely unknown. Reactive oxygen species (ROS) have been recognized for their toxic effects in antimicrobial host defense as well as in aging and carcinogenesis. Enzymes evolved for ROS production belong to the recently discovered NADPH oxidase (Nox) enzyme family . Here we show that the inactivation of a regulatory subunit, NADPH oxidase organizer 1 (Noxo1), resulted in the severe balance deficit seen in the spontaneous mutant "head slant" (hslt) mice whose phenotype was rescued by Noxo1 transgenes. Wild-type Noxo1 was expressed in the vestibular and cochlear epithelia and was required for ROS production by an oxidase complex. In contrast, the hslt mutation of Noxo1 was biochemically inactive and led to an arrest of otoconia genesis, characterized by a complete lack of calcium carbonate mineralization and an accumulation of otoconial protein, otoconin-90/95 (OC-90/95). These results suggest that ROS generated by a Noxo1-dependent vestibular oxidase are critical for otoconia formation and may be required for interactions among otoconial components. Noxo1 mutants implicate a constructive developmental role for ROS, in contrast to their previously described toxic effects.
authors.affiliation: Department of Anatomy and Cell Biology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, 52242, USA.
authors.forename: Péter J
authors.initials: PJ
authors.lastname: Kiss
authors.forename: Judit
authors.initials: J
authors.lastname: Knisz
authors.forename: Yuzhou
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jonas
authors.initials: J
authors.lastname: Baltrusaitis
authors.forename: Curt D
authors.initials: CD
authors.lastname: Sigmund
authors.forename: Ruediger
authors.initials: R
authors.lastname: Thalmann
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Verpy
authors.forename: Botond
authors.initials: B
authors.lastname: Bánfi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000502:physiology; D000818:Animals; D002135:Calcium-Binding Proteins; D002460:Cell Line; D007758:Ear, Inner / Q000378:metabolism; D016326:Extracellular Matrix Proteins; D016368:Frameshift Mutation; D006023:Glycoproteins / Q000032:analysis / Q000378:metabolism; D006801:Humans; D051379:Mice; D010037:Otolithic Membrane / Q000737:chemistry / Q000196:embryology* / Q000378:metabolism; D004856:Postural Balance / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D019076:Transgenes
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C476419:NOXO1 protein, human; C472287:Noxo1 protein, mouse; C116608:OC90 protein, human; C512837:Oc90 protein, mouse; D011506:Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species