Inactivation of NADPH oxidase organizer 1 results in severe imbalance. Curr Biol 2006 Jan 24;16(2):208-13
Date
01/25/2006Pubmed ID
16431374DOI
10.1016/j.cub.2005.12.025Scopus ID
2-s2.0-30944460667 (requires institutional sign-in at Scopus site) 93 CitationsAbstract
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.
Author List
Kiss PJ, Knisz J, Zhang Y, Baltrusaitis J, Sigmund CD, Thalmann R, Smith RJ, Verpy E, Bánfi BAuthor
Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Adaptor Proteins, Signal TransducingAdaptor Proteins, Vesicular Transport
Animals
Calcium-Binding Proteins
Cell Line
Ear, Inner
Extracellular Matrix Proteins
Frameshift Mutation
Glycoproteins
Humans
Mice
Otolithic Membrane
Postural Balance
Proteins
RNA, Messenger
Reactive Oxygen Species
Transgenes
