Unknown

Dataset Information

0

A claudin-9-based ion permeability barrier is essential for hearing.


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.

SUBMITTER: Nakano Y 

PROVIDER: S-EPMC2720454 | BioStudies | 2009-01-01

REPOSITORIES: biostudies

Similar Datasets

2006-01-01 | S-EPMC1698716 | BioStudies
2018-01-01 | S-EPMC6123731 | BioStudies
2019-01-01 | S-EPMC6769696 | BioStudies
2019-01-01 | S-EPMC6745279 | BioStudies
2012-01-01 | S-EPMC3694388 | BioStudies
1000-01-01 | S-EPMC3754262 | BioStudies
2008-01-01 | S-EPMC2413111 | BioStudies
2015-01-01 | S-EPMC4659823 | BioStudies
2017-01-01 | S-EPMC5554435 | BioStudies
2019-01-01 | S-EPMC6379431 | BioStudies