Journal Club: Endocochlear potential kills hair cells in the TMPRSS3 mutant mice cochlea - by lowering the endocochlear potential, can we protect hair cells?

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Today's journal article

Shearer AE, Chen YS, Rouse SL, Wang X, Marin Fermin J, Booth KT, Moawad J, Libiran NB, Li J, Kim HY, Hoa M, Olszewski R, Lei JY, Cabrera E, Totten DJ, Zhao B, Holt JR, Nelson RF. Endocochlear potential contributes to hair cell death in TMPRSS3 hearing loss. 

Why I picked this article

This research investigates the role of endocochlear potential, the voltage that drives sound signal transduction, in the rapid hair cell degeneration seen in a model of hearing loss caused by the TMPRSS3 mutation. 

There are over 120 genes known to cause hereditary or familial hearing loss. The gene TMPRSS3 is a well-known cause of hereditary deafness, including both early-onset (DFNB10) and progressive post-lingual hearing loss (DFNB8). For those two conditions (DFNB10 and DFNB8), we still don’t fully understand how TMPRSS3 mutations lead to hearing loss. 

The TMPRSS3 gene is a template for producing a protein, TMPRSS3; the Transmembrane serine protease III. TMPRSS3 in the cochlea is found in inner and outer hair cells, and a group of auditory neurons (spiral ganglion neurons type II). When TMPRSS3 is deficient, hair cells rapidly degenerate, and the loss of sensory cells causes profound hearing loss. The timing of hair cell loss in TMPRSS3 deficiency coincides with when the ionic environment in the cochlea matures enough to have "endocochlear potential". Endocochlear potential acts as the battery for the cochlea in detecting sounds. Based on the previous research, this research investigated the hypothesis that endocochlear potential may play a part in the degeneration of hair cells in the TMPRSS3-deficient cochlea. 

Some of the research findings

Animal Model: Tmprss3 Y260X/Y260X mice

  • Tmprss3 Y260X/Y260X mice: These genetically modified mice mimic human TMPRSS3 hearing loss.
  • In these mice, the development of auditory neurons was normal. 
  • In these mice, hair cell development was normal, but hair cells were lost rapidly between postnatal day 12 to 14 (P12–P14) in animals (in vivo). 
  • However, when cultured in vitro (i.e., the cochlea was taken out and cultured), hair cells lived for a longer period of time. 
  • The timing of hair cell death coincided with an increase in endocochlear potential as directly measured in the animal. 

Rescue by reducing the endocochlear potential:

  • Tmprss3Y260X/Y260X;Mitf+/Mi-wh double-mutant mice were generated. They will have less endocochlear potential (<20mV). 
  • Tmprss3Y260X/Y260X;Pou3f4delJ/Y(male) or Tmprss3Y260X/Y260X.;Pou3f4delJ/delJ (female) double-mutant mice were generated. In these mice, endocochlear potential is lower than normal (<38mV). 
  • In both cases, hair cells were preserved a lot more than Tmprss3Y260X/Y260X mice. 
  • By analysing surviving hair cells in the combination mutants, researchers found that the Tmprss3Y260X/Y260X mutation seems to cause loss of the potassium channel protein, KCNMA1, from hair cells. 
  • Furthermore, using a drug, furosemide, to reduce endocochlear potential also rescued some hair cell loss in Tmprss3Y260X/Y260X mice.
Taken together, the data suggest that the endocochlear potential seems to be a trigger for degeneration in this model of deafness caused by TMPRSS3 mutation. 
Figure 4D. The endocochlear potential in normal (WT) and different transgenic mice. This is such useful graph!! Shearer e al. (2025). 

Haruna's takeaway

This is a very nice research publication! We often focus on genes and cell structure, but this study reminds us that electrical environments within the cochlea, like the endocochlear potential, are just as crucial. When cells die really early in the development, like the example of Tmprss3Y260X/Y260X mice or in many other knockout mice, it is very difficult to understand what exactly caused the death of the cell. This is because cells are dead too early to do any functional tests, and it is hard to differentiate between a developmental defect and post-developmental pathology. In this research, the double-crossing of transgenic mice to generate a version of mice where TMPRSS3 was mutated but had a lower endocochlear potential allowed further investigation. It was also very clever approach to first test the difference using long-term culture of the Tmprss3Y260X/Y260X mice cochlea in vitro, which is also very difficult. 

The concept of using drug treatment to manipulate endocochlear potential purposefully to preserve the hair cell from death is very interesting. It may allow preservation of cells long enough to open the therapeutic window, to allow gene therapy, perhaps? Looking forward to reading follow-up studies and more studies like this one. 

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This is Haruna's 37/100 of the 100-day challenge to post a science blog article every day! I love inner ear biology & cochlear physiology.