Hearing loss caused by progressive degeneration of cochlear hair cells in mice deficient for the Barhl1 homeobox gene

Development ◽  
2002 ◽  
Vol 129 (14) ◽  
pp. 3523-3532 ◽  
Author(s):  
Shengguo Li ◽  
Sandy M. Price ◽  
Hugh Cahill ◽  
David K. Ryugo ◽  
Michael M. Shen ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Inner Ear ◽  
Hair Cells ◽  
Organ Of Corti ◽  
Cochlear Hair Cells ◽  
Sensory Hair ◽  
Progressive Degeneration ◽  
Age Related ◽  
Sensory Hair Cells

The cochlea of the mammalian inner ear contains three rows of outer hair cells and a single row of inner hair cells. These hair cell receptors reside in the organ of Corti and function to transduce mechanical stimuli into electrical signals that mediate hearing. To date, the molecular mechanisms underlying the maintenance of these delicate sensory hair cells are unknown. We report that targeted disruption of Barhl1, a mouse homolog of the Drosophila BarH homeobox genes, results in severe to profound hearing loss, providing a unique model for the study of age-related human deafness disorders. Barhl1 is expressed in all sensory hair cells during inner ear development, 2 days after the onset of hair cell generation. Loss of Barhl1 function in mice results in age-related progressive degeneration of both outer and inner hair cells in the organ of Corti, following two reciprocal longitudinal gradients. Our data together indicate an essential role for Barhl1 in the long-term maintenance of cochlear hair cells, but not in the determination or differentiation of these cells.

The role of Math1 in inner ear development: Uncoupling the establishment of the sensory primordium from hair cell fate determination

Development ◽  
2002 ◽  
Vol 129 (10) ◽  
pp. 2495-2505 ◽  
Author(s):  
Ping Chen ◽  
Jane E. Johnson ◽  
Huda Y. Zoghbi ◽  
Neil Segil
Keyword(s):  
Hair Cell ◽  
Inner Ear ◽  
Cell Fate ◽  
Hair Cells ◽  
Organ Of Corti ◽  
Sensory Epithelium ◽  
Proliferating Cells ◽  
Sensory Hair ◽  
Sensory Hair Cells ◽  
Hair Cell Differentiation

During embryonic development of the inner ear, the sensory primordium that gives rise to the organ of Corti from within the cochlear epithelium is patterned into a stereotyped array of inner and outer sensory hair cells separated from each other by non-sensory supporting cells. Math1, a close homolog of the Drosophila proneural gene atonal, has been found to be both necessary and sufficient for the production of hair cells in the mouse inner ear. Our results indicate that Math1 is not required to establish the postmitotic sensory primordium from which the cells of the organ of Corti arise, but instead is limited to a role in the selection and/or differentiation of sensory hair cells from within the established primordium. This is based on the observation that Math1 is only expressed after the appearance of a zone of non-proliferating cells that delineates the sensory primordium within the cochlear anlage. The expression of Math1 is limited to a subpopulation of cells within the sensory primordium that appear to differentiate exclusively into hair cells as the sensory epithelium matures and elongates through a process that probably involves radial intercalation of cells. Furthermore, mutation of Math1 does not affect the establishment of this postmitotic sensory primordium, even though the subsequent generation of hair cells is blocked in these mutants. Finally, in Math1 mutant embryos, a subpopulation of the cells within the sensory epithelium undergo apoptosis in a temporal gradient similar to the basal-to-apical gradient of hair cell differentiation that occurs in the cochlea of wild-type animals.

scholarly journals Putative pore-forming subunits of the mechano-electrical transduction channel, Tmc1/2b, require Tmie to localize to the site of mechanotransduction in zebrafish sensory hair cells

2018 ◽  
Author(s):  
Itallia V. Pacentine ◽  
Teresa Nicolson
Keyword(s):  
Hair Cell ◽  
Inner Ear ◽  
Hair Cells ◽  
Transmembrane Domain ◽  
Cell Activity ◽  
Sensory Hair ◽  
Transmembrane Channel ◽  
Extracellular Region ◽  
Normal Site ◽  
Sensory Hair Cells

AbstractMutations 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 putative subunits of the MET channel, fail to target to the hair bundle. In contrast, overexpression of Tmie strongly enhances the targeting of 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 mediates 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 subunits to the site of MET.Author summaryHair cells mediate hearing and balance through the activity of a pore-forming channel in the cell membrane. The transmembrane inner ear (TMIE) protein is an essential component of the protein complex that gates this so-called mechanotransduction channel. While it is known that loss of TMIE results in deafness, the function of TMIE within the complex is unclear. Using zebrafish as a deafness model, Pacentine and Nicolson demonstrate that Tmie is required for the localization of other essential complex members, the transmembrane channel-like (Tmc) proteins, Tmc1/2b. They then evaluate twelve unique versions of Tmie, each containing mutations to different domains of Tmie. This analysis reveals that some mutations in Tmie cause dysfunctional gating of the channel as demonstrated through reduced hair cell activity, and that these same dysfunctional versions also display reduced Tmc expression at the normal site of the channel. These findings link hair cell activity with the levels of Tmc in the bundle, reinforcing the currently-debated notion that the Tmcs are the pore-forming subunits of the mechanotransduction channel. The authors conclude that Tmie, through distinct regions, is involved in both trafficking and stabilizing the Tmcs at the site of mechanotransduction.

scholarly journals Identification of a 275-kD protein associated with the apical surfaces of sensory hair cells in the avian inner ear.

1990 ◽  
Vol 110 (4) ◽  
pp. 1055-1066 ◽  
Author(s):  
G P Richardson ◽  
S Bartolami ◽  
I J Russell
Keyword(s):  
Hair Cell ◽  
Inner Ear ◽  
Hair Cells ◽  
Proximal Region ◽  
Basilar Papilla ◽  
Relative Molecular Mass ◽  
Apical Surface ◽  
Sensory Hair ◽  
Sensory Hair Cells ◽  
Avian Inner Ear

Immunological techniques have been used to generate both polyclonal and monoclonal antibodies specific for the apical ends of sensory hair cells in the avian inner ear. The hair cell antigen recognized by these antibodies is soluble in nonionic detergent, behaves on sucrose gradients primarily as a 16S particle, and, after immunoprecipitation, migrates as a polypeptide with a relative molecular mass of 275 kD on 5% SDS gels under reducing conditions. The antigen can be detected with scanning immunoelectron microscopy on the apical surface of the cell and on the stereocilia bundle but not on the kinocilium. Double label studies indicate that the entire stereocilia bundle is stained in the lagena macula (a vestibular organ), whereas in the basilar papilla (an auditory organ) only the proximal region of the stereocilia bundle nearest to the apical surface is stained. The monoclonal anti-hair cell antibodies do not stain brain, tongue, lung, liver, heart, crop, gizzard, small intestine, skeletal muscle, feather, skin, or eye tissues but do specifically stain renal corpuscles in the kidney. Experiments using organotypic cultures of the embryonic lagena macula indicate that the antibodies cause a significant increase in the steady-state stiffness of the stereocilia bundle but do not inhibit mechanotransduction. The antibodies should provide a suitable marker and/or tool for the purification of the apical sensory membrane of the hair cell.

scholarly journals Deletion of Clusterin Protects Cochlear Hair Cells against Hair Cell Aging and Ototoxicity

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Xiaochang Zhao ◽  
Heidi J. Henderson ◽  
Tianying Wang ◽  
Bo Liu ◽  
Yi Li
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Sensorineural Hearing Loss ◽  
Hair Cells ◽  
Sensorineural Hearing ◽  
Cell Aging ◽  
Supporting Cells ◽  
Drug Induced ◽  
Cochlear Hair Cells ◽  
Age Related

Hearing loss is a debilitating disease that affects 10% of adults worldwide. Most sensorineural hearing loss is caused by the loss of mechanosensitive hair cells in the cochlea, often due to aging, noise, and ototoxic drugs. The identification of genes that can be targeted to slow aging and reduce the vulnerability of hair cells to insults is critical for the prevention of sensorineural hearing loss. Our previous cell-specific transcriptome analysis of adult cochlear hair cells and supporting cells showed that Clu, encoding a secreted chaperone that is involved in several basic biological events, such as cell death, tumor progression, and neurodegenerative disorders, is expressed in hair cells and supporting cells. We generated Clu-null mice (C57BL/6) to investigate its role in the organ of Corti, the sensory epithelium responsible for hearing in the mammalian cochlea. We showed that the deletion of Clu did not affect the development of hair cells and supporting cells; hair cells and supporting cells appeared normal at 1 month of age. Auditory function tests showed that Clu-null mice had hearing thresholds comparable to those of wild-type littermates before 3 months of age. Interestingly, Clu-null mice displayed less hair cell and hearing loss compared to their wildtype littermates after 3 months. Furthermore, the deletion of Clu is protected against aminoglycoside-induced hair cell loss in both in vivo and in vitro models. Our findings suggested that the inhibition of Clu expression could represent a potential therapeutic strategy for the alleviation of age-related and ototoxic drug-induced hearing loss.

scholarly journals Codeficiency of Lysosomal Mucolipins 3 and 1 in Cochlear Hair Cells Diminishes Outer Hair Cell Longevity and Accelerates Age-Related Hearing Loss

2018 ◽  
Vol 38 (13) ◽  
pp. 3177-3189 ◽  
Author(s):  
Teerawat Wiwatpanit ◽  
Natalie N. Remis ◽  
Aisha Ahmad ◽  
Yingjie Zhou ◽  
John C. Clancy ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Hair Cells ◽  
Outer Hair Cell ◽  
Cochlear Hair Cells ◽  
Age Related ◽  
Age Related Hearing Loss ◽  
Cell Longevity

Regeneration of sensory hair cells after acoustic trauma

Science ◽  
1988 ◽  
Vol 240 (4860) ◽  
pp. 1772-1774 ◽  
Author(s):  
JT Corwin ◽  
DA Cotanche
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Acoustic Trauma ◽  
Sensory Cells ◽  
Lesion Site ◽  
Supporting Cells ◽  
Profound Hearing Loss ◽  
Cochlear Hair Cells ◽  
Sensory Hair ◽  
Sensory Hair Cells

Any loss of cochlear hair cells has been presumed to result in a permanent hearing deficit because the production of these cells normally ceases before birth. However, after acoustic trauma, injured sensory cells in the mature cochlea of the chicken are replaced. New cells appear to be produced by mitosis of supporting cells that survive at the lesion site and do not divide in the absence of trauma. This trauma-induced division of normally postmitotic cells may lead to recovery from profound hearing loss.

scholarly journals Noise-induced and age-related hearing loss:  new perspectives and potential therapies

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 927 ◽  
Author(s):  
M Charles Liberman
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Sensorineural Hearing Loss ◽  
Hair Cells ◽  
Auditory Nerve ◽  
Cell Loss ◽  
Sensorineural Hearing ◽  
Hair Cell Loss ◽  
Age Related ◽  
Age Related Hearing Loss

The classic view of sensorineural hearing loss has been that the primary damage targets are hair cells and that auditory nerve loss is typically secondary to hair cell degeneration. Recent work has challenged that view. In noise-induced hearing loss, exposures causing only reversible threshold shifts (and no hair cell loss) nevertheless cause permanent loss of >50% of the synaptic connections between hair cells and the auditory nerve. Similarly, in age-related hearing loss, degeneration of cochlear synapses precedes both hair cell loss and threshold elevation. This primary neural degeneration has remained a “hidden hearing loss” for two reasons: 1) the neuronal cell bodies survive for years despite loss of synaptic connection with hair cells, and 2) the degeneration is selective for auditory nerve fibers with high thresholds. Although not required for threshold detection when quiet, these high-threshold fibers are critical for hearing in noisy environments. Research suggests that primary neural degeneration is an important contributor to the perceptual handicap in sensorineural hearing loss, and it may be key to the generation of tinnitus and other associated perceptual anomalies. In cases where the hair cells survive, neurotrophin therapies can elicit neurite outgrowth from surviving auditory neurons and re-establishment of their peripheral synapses; thus, treatments may be on the horizon.

scholarly journals Effects of cochlear hair cell ablation on spatial learning/memory

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Z. Jason Qian ◽  
Anthony J. Ricci
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Spatial Learning ◽  
Hair Cells ◽  
Noise Exposure ◽  
Memory Errors ◽  
Cochlear Hair Cells ◽  
Cochlear Hair Cell ◽  
Cell Ablation ◽  
Spatial Learning Memory

AbstractCurrent clinical interest lies in the relationship between hearing loss and cognitive impairment. Previous work demonstrated that noise exposure, a common cause of sensorineural hearing loss (SNHL), leads to cognitive impairments in mice. However, in noise-induced models, it is difficult to distinguish the effects of noise trauma from subsequent SNHL on central processes. Here, we use cochlear hair cell ablation to isolate the effects of SNHL. Cochlear hair cells were conditionally and selectively ablated in mature, transgenic mice where the human diphtheria toxin (DT) receptor was expressed behind the hair-cell specific Pou4f3 promoter. Due to higher Pou4f3 expression in cochlear hair cells than vestibular hair cells, administration of a low dose of DT caused profound SNHL without vestibular dysfunction and had no effect on wild-type (WT) littermates. Spatial learning/memory was assayed using an automated radial 8-arm maze (RAM), where mice were trained to find food rewards over a 14-day period. The number of working memory errors (WME) and reference memory errors (RME) per training day were recorded. All animals were injected with DT during P30–60 and underwent the RAM assay during P90–120. SNHL animals committed more WME and RME than WT animals, demonstrating that isolated SNHL affected cognitive function. Duration of SNHL (60 versus 90 days post DT injection) had no effect on RAM performance. However, younger age of acquired SNHL (DT on P30 versus P60) was associated with fewer WME. This describes the previously undocumented effect of isolated SNHL on cognitive processes that do not directly rely on auditory sensory input.

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