Kiss Péter J, Knisz Judit, Zhang Yuzhou, Baltrusaitis Jonas, Sigmund Curt D, Thalmann Ruediger, Smith Richard J H, Verpy Elisabeth, Bánfi Botond
Department of Anatomy and Cell Biology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, 52242, USA.
Curr Biol. 2006 Jan 24;16(2):208-13. doi: 10.1016/j.cub.2005.12.025.
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.
耳石是前庭系统的生物矿物质，对重力感知不可或缺。尽管其很重要，但耳石形成过程在很大程度上仍不清楚。活性氧（ROS）在抗菌宿主防御以及衰老和致癌过程中的毒性作用已得到认可。进化出用于产生ROS的酶属于最近发现的NADPH氧化酶（Nox）酶家族。在这里我们表明，调节亚基NADPH氧化酶组织者1（Noxo1）的失活导致了自发突变体“头部倾斜”（hslt）小鼠出现严重的平衡缺陷，其表型可通过Noxo1转基因得到挽救。野生型Noxo1在前庭和耳蜗上皮中表达，是氧化酶复合物产生ROS所必需的。相比之下，Noxo1的hslt突变在生化上无活性，并导致耳石形成停滞，其特征是完全缺乏碳酸钙矿化以及耳石蛋白耳石素-90/95（OC-90/95）的积累。这些结果表明，由Noxo1依赖性前庭氧化酶产生的ROS对耳石形成至关重要，可能是耳石成分之间相互作用所必需的。与之前描述的毒性作用相反，Noxo1突变体暗示了ROS在发育过程中的建设性作用。
