Using the Zebrafish Lateral Line to Understand the Roles of Mitochondria in Sensorineural Hearing Loss
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Abstract:
Hair cells are the mechanosensory receptors of the inner ear and can be damaged by noise, aging, and ototoxic drugs. This damage often results in permanent sensorineural hearing loss. Hair cells have high energy demands and rely on mitochondria to produce ATP as well as contribute to intracellular calcium homeostasis. In addition to generating ATP, mitochondria produce reactive oxygen species, which can lead to oxidative stress, and regulate cell death pathways. Zebrafish lateral-line hair cells are structurally and functionally analogous to cochlear hair cells but are optically and pharmacologically accessible within an intact specimen, making the zebrafish a good model in which to study hair-cell mitochondrial activity. Moreover, the ease of genetic manipulation of zebrafish embryos allows for the study of mutations implicated in human deafness, as well as the generation of transgenic models to visualize mitochondrial calcium transients and mitochondrial activity in live organisms. Studies of the zebrafish lateral line have shown that variations in mitochondrial activity can predict hair-cell susceptibility to damage by aminoglycosides or noise exposure. In addition, antioxidants have been shown to protect against noise trauma and ototoxic drug–induced hair-cell death. In this review, we discuss the tools and findings of recent investigations into zebrafish hair-cell mitochondria and their involvement in cellular processes, both under homeostatic conditions and in response to noise or ototoxic drugs. The zebrafish lateral line is a valuable model in which to study the roles of mitochondria in hair-cell pathologies and to develop therapeutic strategies to prevent sensorineural hearing loss in humans.Keywords:
Calcium imaging
Live cell imaging
Bromodeoxyuridine
Ototoxicity
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Abstract Here we present spatio-temporal localization of Kremen1, a transmembrane receptor, in the mammalian cochlea and investigate its role in the formation of sensory organs in mammal and fish model organisms. We show that Kremen1 is expressed in prosensory cells during cochlear development and in supporting cells of the adult mouse cochlea. Based on this expression pattern, we investigated whether Kremen1 functions to modulate cell fate decisions in the prosensory domain of the developing cochlea. We used gain and loss-of-function experiments to show that Kremen1 is sufficient to bias cells towards supporting cell fate and is implicated in suppression of hair cell formation. In addition to our findings in the mouse cochlea, we examined the effects of over expression and loss of Kremen1 in the zebrafish lateral line. In agreement with our mouse data, we show that over expression of Kremen1 has a negative effect on the number of mechanosensory cells that form in the zebrafish neuromasts and that fish lacking Kremen1 protein develop more hair cells per neuromast compared to wild type fish. Collectively, these data support an inhibitory role for Kremen1 in hair cell fate specification.
Lateral line
Cell fate determination
Cell type
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Neomycin
Degeneration (medical)
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Hair cell regeneration in the inner ear: a review Hair cell regeneration has been shown to occur in the inner ear of mammals. Specifically, it has been demonstrated in the vestibular system and not the organ of Corti. Recent evidence suggests that the degree of the regenerative response may be augmented pharmacologically. This review discusses the field of hair cell regeneration in fish, amphibians, birds and mammals, and the relationship of regeneration to functional recovery
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Efferent nerve
Stereocilia (inner ear)
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• Chinchillas were exposed to octave band noise, sodium salicylate (300 mg/kg per day intraperitoneally), or the combination of both agents for 15 days. The octave band noise exposure was centered at 500 Hz at an intensity of either 80 or 105 dB sound pressure level. The effects of the experimental treatments were evaluated by determining the number of missing hair cells after recovery as a function of location within the cochlea using a surface preparation technique. Average cochleograms were calculated for each of five experimental groups. Animals given salicylate alone showed little or no hair cell loss. Noise exposure at 80 dB resulted in a mild (<30%) outer hair cell loss in the apical turn of the cochlea, whereas exposure at 105 dB resulted in moderate (50%) outer hair cell loss (outer hair cell first row particularly) in the apical half of the cochlea, mild outer hair cell loss in the basal region of the cochlea, and a mild loss of inner hair cells. The amount of hair cell loss in the groups exposed to the combination of salicylates and noise was not significantly different from the corresponding groups exposed to noise alone. Statistical analysis of the data suggest that the combination of salicylate plus noise does not produce any greater hair cell loss than noise alone. (Arch Otolaryngol Head Neck Surg. 1992;118:157-164)
Chinchilla
Octave band
Sodium salicylate
Noise-induced hearing loss
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Kinocilium
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