Libiran : Reduced Endocochlear Potential in vivo Prevents Hair Cell Degeneration in Tmprss3-deficient Mice
Reduced Endocochlear Potential in vivo Prevents Hair Cell Degeneration in Tmprss3-deficient Mice
Nicole Bianca Libiran
Indiana University School of Medicine, Indianapolis, IN
Nicole Bianca Libiran, Indiana University School of Medicine, Indianapolis, IN; Ernesto Cabrera, Indiana University School of Medicine, Indianapolis, IN; Yuan-Siao Chen, Indiana University School of Medicine, Indianapolis, IN; Rick Nelson, Indiana University School of Medicine, Department of Otolaryngology, Indianapolis, Indiana
Transmembrane serine protease 3 (TMPRSS3) is a transmembrane serine protease with proteolytic activity essential for normal auditory function in mice and humans. Tmprss3-mutant mice exhibit normal hair cell (HC) development until postnatal day 12 (P12), followed by rapid HC degeneration within 48 hours, resulting in deafness. The HC degeneration temporally correlates with the rapid rise in endocochlear potential (EP) that is required for hearing. This phenotype mirrors other mouse models with defects in genes expressing tight junctions (TJs). Thus, we hypothesize that TMPRSS3 regulates tight junctions and cell death is mediated through high EP.
Here we investigated the role of EP in Tmprss3-deficient mice using in vivo experiments. We crossed the Tmprss3-mutant mice with Pou3f4-mutant mice, which fail to generate EP. Cochlear whole mounts were dissected, fixed, and stained for four groups of mice: wild-type, Tmprss3-mutant, Pou3f4-mutant, and double-mutant mice. Inner and outer hair cells were quantified within a span of 125 µm and compared between groups.
We found significant preservation of HCs (p<0.001) in double mutant mice with reduced EP compared to Tmprss3-mutant mice.
HC degeneration in Tmprss3-deficient mice is due to endocochlear potential driven K+ toxicity. Tmprss3-deficient mice likely have faulty apical TJs that result in leakage of K+ ions from the endolymph to the basolateral side of HCs, leading to HC degeneration. Future research should work to elucidate TMPRSS3’s proteolytic target and its mechanism of TJ-related regulation.
Translational/Human Health Impact:
These findings have large implications for potential therapeutic approaches in patients with Tmprss3 mutations. For instance, this implies that clinicians can reduce endocochlear potential in humans using a drug like furosemide to buy time before hair cells degenerate. Patients with a partially functional TMPRSS3 have hearing loss at higher frequencies at cochlea’s base, thus implicating Tmprss3 gene modulation as a potential gene therapy approach.