Journal article
A claudin-9-based ion permeability barrier is essential for hearing
PLoS genetics, Vol.5(8), pp.e1000610-e1000610
08/2009
DOI: 10.1371/journal.pgen.1000610
PMCID: PMC2720454
PMID: 19696885
Abstract
Hereditary hearing loss is one of the most common birth defects, yet the majority of genes required for audition is thought to remain unidentified. Ethylnitrosourea (ENU)-mutagenesis has been a valuable approach for generating new animal models of deafness and discovering previously unrecognized gene functions. Here we report on the characterization of a new ENU-induced mouse mutant (nmf329) that exhibits recessively inherited deafness. We found a widespread loss of sensory hair cells in the hearing organs of nmf329 mice after the second week of life. Positional cloning revealed that the nmf329 strain carries a missense mutation in the claudin-9 gene, which encodes a tight junction protein with unknown biological function. In an epithelial cell line, heterologous expression of wild-type claudin-9 reduced the paracellular permeability to Na+ and K+, and the nmf329 mutation eliminated this ion barrier function without affecting the plasma membrane localization of claudin-9. In the nmf329 mouse line, the perilymphatic K+ concentration was found to be elevated, suggesting that the cochlear tight junctions were dysfunctional. Furthermore, the hair-cell loss in the claudin-9-defective cochlea was rescued in vitro when the explanted hearing organs were cultured in a low-K+ milieu and in vivo when the endocochlear K+-driving force was diminished by deletion of the pou3f4 gene. Overall, our data indicate that claudin-9 is required for the preservation of sensory cells in the hearing organ because claudin-9-defective tight junctions fail to shield the basolateral side of hair cells from the K+-rich endolymph. In the tight-junction complexes of hair cells, claudin-9 is localized specifically to a subdomain that is underneath more apical tight-junction strands formed by other claudins. Thus, the analysis of claudin-9 mutant mice suggests that even the deeper (subapical) tight-junction strands have biologically important ion barrier function.
Details
- Title: Subtitle
- A claudin-9-based ion permeability barrier is essential for hearing
- Creators
- Yoko Nakano - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa, USASung H KimHyoung-Mi KimJoel D SannemanYuzhou ZhangRichard J H SmithDaniel C Marcus - Kansas State UniversityPhiline WangemannRandy A NesslerBotond Bánfi
- Resource Type
- Journal article
- Publication Details
- PLoS genetics, Vol.5(8), pp.e1000610-e1000610
- DOI
- 10.1371/journal.pgen.1000610
- PMID
- 19696885
- PMCID
- PMC2720454
- NLM abbreviation
- PLoS Genet
- ISSN
- 1553-7390
- eISSN
- 1553-7404
- Publisher
- Public Library Science; United States
- Grant note
- DC002842 / NIDCD NIH HHS P20-RR017686 / NCRR NIH HHS P30 DK-54759 / NIDDK NIH HHS P20 RR017686 / NCRR NIH HHS R01-DC01098 / NIDCD NIH HHS R01 DC000212 / NIDCD NIH HHS R01-DC00212 / NIDCD NIH HHS R01 DC002842 / NIDCD NIH HHS DCO3544 / PHS HHS R01 DC001098 / NIDCD NIH HHS P30 DK054759 / NIDDK NIH HHS
- Language
- English
- Date published
- 08/2009
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
- Record Identifier
- 9984006418602771
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