Abstract
Mutations in transmembrane inner ear (TMIE) cause deafness in humans; previous studies suggest involvement in the mechano-electrical transduction (MET) complex in sensory hair cells, but TMIE’s precise role is unclear. In tmie zebrafish mutants, we observed that GFP-tagged Tmc1 and Tmc2b, which are subunits of the MET channel, fail to target to the hair bundle. In contrast, overexpression of Tmie strongly enhances the targeting of Tmc1-GFP and Tmc2b-GFP to stereocilia. To identify the motifs of Tmie underlying the regulation of the Tmcs, we systematically deleted or replaced peptide segments. We then assessed localization and functional rescue of each mutated/chimeric form of Tmie in tmie mutants. We determined that the first putative helix was dispensable and identified a novel critical region of Tmie, the extracellular region and transmembrane domain, which is required for both mechanosensitivity and Tmc2b-GFP expression in bundles. Collectively, our results suggest that Tmie’s role in sensory hair cells is to target and stabilize Tmc channel subunits to the site of MET.
Highlights
The auditory and vestibular systems detect mechanical stimuli such as sound, gravity, and acceleration
Earlier studies proposed a developmental role for transmembrane inner ear (TMIE) [21,22,23], while later studies evidenced a role in mechano-electrical transduction (MET) [26, 27]
To begin our analysis and attempt to clarify the issue in zebrafish, we examined live tmieru1000 larvae at 5–7 days postfertilization using confocal microscopy
Summary
The auditory and vestibular systems detect mechanical stimuli such as sound, gravity, and acceleration. When tension is placed on the upper-most linkages known as tip links, the force is thought to open mechanosensitive channels at the distal end of the shorter stereocilia [2, 3]. These channels pass current, depolarizing the cell and permitting electrical output to the brain via the eighth cranial nerve. While a handful of essential members of this MET complex have been identified, we do not fully understand how all of these proteins interact It is not known how the MET channel is localized to and maintained at the stereocilia tips
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