The transmembrane inner ear (Tmie) protein is essential for normal hearing and balance in the zebrafish

Abstract

Little is known about the proteins that mediate mechanoelectrical transduction, the process by which acoustic and accelerational stimuli are transformed by hair cells of the inner ear into electrical signals. In our search for molecules involved in mechanotransduction, we discovered a line of deaf and uncoordinated zebrafish with defective hair-cell function. The hair cells of mutant larvae fail to incorporate fluorophores that normally traverse the transduction channels and their ears lack microphonic potentials in response to vibratory stimuli. Hair cells in the posterior lateral lines of mutants contain numerous lysosomes and have short, disordered hair bundles. Their stereocilia lack two components of the transduction apparatus, tip links and insertional plaques. Positional cloning revealed an early frameshift mutation in tmie, the zebrafish ortholog of the mammalian gene transmembrane inner ear. The mutant line therefore affords us an opportunity to investigate the role of the corresponding protein in mechanoelectrical transduction.auditory system ͉ hair cell ͉ lateral line ͉ mechanoelectrical transduction ͉ vestibular system T he vertebrate inner ear is a complex organ that houses the delicate mechanoreceptors for hearing and balance known as hair cells. Situated at the apical surface of each hair cell is an array of height-ordered stereocilia called the hair bundle. This mechanically sensitive organelle responds in a directiondependent manner to displacements caused by sound and acceleration (1). Deflection of the hair bundle toward its tall edge increases the open probability of transduction channels residing at the stereociliary tips, allowing a depolarizing inward current of cations from the surrounding endolymph. Bundle movement in the opposite direction has the opposite effect, hyperpolarizing the hair cell. The conversion of acoustic and accelerational stimuli into electrical signals that are transmitted to the auditory nerve and subsequently to the brain is known as mechanoelectrical transduction.Although we have a basic understanding of the biophysical and electrophysiological events that initiate hearing, we know much less about the molecules involved. The difficulty in identifying these components stems from the paucity of sensory tissue in the inner ear, which frustrates biochemical purification and traditional molecular-biological assays. Genetic investigation has therefore largely replaced these approaches as the preferred strategy for identifying proteins important in hearing (2).The zebrafish has proven useful for this purpose (3). The internal ear of the zebrafish, which is anatomically and functionally similar to those of other vertebrates (4), undergoes rapid development and is readily accessible for observation and manipulation owing to its optical transparency. The zebrafish possesses an additional feature useful for hair-cell investigations, the lateral-line system. This apparatus, which comprises a series of hair-cell clusters termed neuromasts distributed over the body surface, is u...

Development and localization of reverse-polarity mechanotransducer channels in cochlear hair cells

“…Thus, biophysical attributes of the normal-polarity and unconventional channels are similar but not identical. If the channels had the same pore, such differences could reflect the presence of other subunits in the normal channel, such as LHFPL5 and TMIE (9,(32)(33)(34). It will be important to establish whether both have the same protein core or are structurally distinct, as this may provide a clue to the functional significance of the unconventional channels.…”

Neuronal Birth Order Identifies a Dimorphic Sensorineural Map

“…The atoh1a_fh282 mutant strain carries a missense mutation, aa126 arginine to tryptophan, and was obtained from C. Moens (Fred Hutchinson Cancer Research Center, Seattle, WA). The tmie_ru01 mutant fish were described previously (Gleason et al, 2009;Faucherre et al, 2010).…”

Early Development of Hearing in Zebrafish

“…Finally, the zebrafish genome has been sequenced, and many human genes are conserved in zebrafish. Particularly, the zebrafish has been used as a unique vertebrate model for studying hearing and balance disorders (Nicolson et al 1998;Ernest et al 2000;Whitfield 2002;Söllner et al 2004;Kappler et al 2004;Nicolson 2005;Shen et al 2008;Gleason et al 2009;Phillips et al 2011;Yariz et al 2012), with its externally exposed hair cells of the lateral line being used for study in hair cell death and regeneration, ototoxicity, and drug screens (Chiu et al 2008;López-Schier et al 2004;Owens et al 2009;Coffin et al 2010;Buck et al 2012).…”