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

Area of Science:

• Genetics
• Neuroscience
• Cell Biology

Background:

• Hereditary hearing loss is a common birth defect, with many causative genes yet to be identified.
• Ethylnitrosourea (ENU)-mutagenesis is a powerful tool for creating animal models of deafness and uncovering novel gene functions.

Purpose of the Study:

• To characterize a new ENU-induced mouse mutant (nmf329) exhibiting recessively inherited deafness.
• To identify the genetic basis of deafness in the nmf329 mutant and elucidate the function of the affected gene in auditory organs.

Main Methods:

• Positional cloning to identify the mutation in the nmf329 mouse line.
• Heterologous expression in epithelial cell lines to assess claudin-9's ion barrier function.
• Analysis of ion concentrations and cochlear structure in mutant mice.
• In vitro and in vivo rescue experiments to confirm the role of claudin-9.

Main Results:

• The nmf329 mutant harbors a missense mutation in the claudin-9 gene.
• Claudin-9 is essential for maintaining Na+ and K+ paracellular permeability in epithelial cells.
• nmf329 mice display elevated perilymphatic K+ and progressive sensory hair cell loss.
• Low-K+ culture and pou3f4 gene deletion rescued hair cell loss, indicating a K+-dependent mechanism.

Conclusions:

• Claudin-9 is critical for auditory sensory cell preservation by ensuring functional cochlear tight junctions.
• Dysfunctional tight junctions due to claudin-9 defects lead to hair cell degeneration.
• The study highlights the importance of subapical tight junction strands, including claudin-9, in maintaining auditory function.