The cells of the sensory epithelium, and not the stria vascularis, are the main cochlear cells related to the genetic pathogenesis of age-related hearing loss
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE234926 | GEO | 2024/01/18
REPOSITORIES: GEO
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Project description:The stria vascularis (SV) is an intricate non-sensory structure composed of multiple cell layers of different origins in the mammalian cochlea. It generates and maintains the endolymph, and therefore is essential for hearing functions. Here, using single cell transcriptomics and transgenic mouse models, we discover that the Shh receptor Ptch1 is required for marginal cell (MC, the epithelial cell layer of SV) differentiation and SV development. During cochlear development, MC differentiation gradually proceeds from cochlear base to apex, resembling the spatiotemporal differentiation pattern of sensory hair cells. Inactivation of Ptch1 leads to an impaired MC differentiation through elevated Gli2 levels, and inhibition of Gli2/Shh signaling activity is a prerequisite for MC differentiation. Single cell transcriptome analyses reveal that MCs are specified as early as E14. Moreover, in the absence of Ptch1, MC precursors are maintained in the progenitor state and differentiation is blocked consequently.
2024-04-03 | GSE217373 | GEO
Project description:SLC26A4 mutations can cause a distinctive hearing loss phenotype with sudden drops and fluctuation in patients. Existing Slc26a4 mutant mouse lines have a profound loss of hearing and vestibular function, with severe inner ear malformations that do not model this human phenotype. In this study, we generated Slc26a4-insufficient mice by manipulation of doxycycline administration to a transgenic mouse line in which all Slc26a4 expression was under the control of doxycycline. Doxycycline was administered from conception to embryonic day 17.5, and then it was discontinued. Auditory brainstem response thresholds showed significant fluctuation of hearing loss from 1 through 3months of age. The endocochlear potential, which is required for inner ear sensory cell function, correlated with auditory brainstem response thresholds. We observed degeneration of stria vascularis intermediate cells, the cells that generate the endocochlear potential, but no other abnormalities within the cochlea. We conclude that fluctuations of hearing result from fluctuations of the endocochlear potential and stria vascularis dysfunction in Slc26a4-insufficient mouse ears. This model can now be used to test potential interventions to reduce or prevent sudden hearing loss or fluctuation in human patients. Our strategy to generate a hypomorphic mouse model utilizing the tet-on system will be applicable to other diseases in which a hypomorphic allele is needed to model the human phenotype.
| S-EPMC3995827 | biostudies-literature
Project description:Age-related hearing loss is a progressive sensorineural hearing loss that occurs as people get older. Degeneration of the organ of Corti and atrophy of the lateral wall of the cochlear duct (or scala media) in the inner ear are the two primary causes. MicroRNAs (miRNAs), a class of short non-coding RNAs that regulate the expression of mRNA/protein targets, are important regulators of cellular senescence and aging. We examined the change of miRNA gene expression profiles in the lateral wall of the cochlear duct in two mouse strains during aging The totoal RNA was extracted from the lateral wall of cochlear duct from CBA/J and C57BL/6J mice at different ages. The expression profile of miRNAs was examined by miR microarray GeneChip.
2014-10-01 | E-GEOD-57782 | biostudies-arrayexpress
Project description:The endocochlear potential (EP) is essential to hearing, because it provides approximately half of the driving force for the mechanoelectrical transduction current in auditory hair cells. The EP is produced by the stria vascularis (SV), a vascularized bilayer epithelium of the cochlea lateral wall. The absence of the gap junction protein connexin30 (Cx30) in Cx30(-/-) mice results in the SV failure to produce an EP, which mainly accounts for the severe congenital hearing impairment of these mice. Here, we show that the SV components of the EP electrogenic machinery and the epithelial barriers limiting the intrastrial fluid space, which are both necessary for the EP production, were preserved in Cx30(-/-) mice. In contrast, the endothelial barrier of the capillaries supplying the SV was disrupted before EP onset. This disruption is expected to result in an intrastrial electric shunt that is sufficient to account for the absence of the EP production. Immunofluorescence analysis of wild-type mice detected Cx30 in the basal and intermediate cells of the SV but not in the endothelial cells of the SV capillaries. Moreover, dye-coupling experiments showed that endothelial cells were not coupled to the SV basal, intermediate, and marginal cells. SV transcriptome analysis revealed a significant down-regulation of betaine homocysteine S-methyltransferase (Bhmt) in the Cx30(-/-) mice, which was restricted to the SV and resulted in a local increase in homocysteine, a known factor of endothelial dysfunction. Disruption of the SV endothelial barrier is a previously undescribed pathogenic process underlying hearing impairment.
| S-EPMC1851033 | biostudies-literature
Project description:Age-related hearing loss is a progressive sensorineural hearing loss that occurs as people get older. Degeneration of the organ of Corti and atrophy of the lateral wall of the cochlear duct (or scala media) in the inner ear are the two primary causes. MicroRNAs (miRNAs), a class of short non-coding RNAs that regulate the expression of mRNA/protein targets, are important regulators of cellular senescence and aging. We examined the change of miRNA gene expression profiles in the lateral wall of the cochlear duct in two mouse strains during aging
2014-10-01 | GSE57782 | GEO
Project description:Evaluation of transcriptional changes in the E14.5 cochlear duct epithelium upon tamoxifen-induced loss of Tbx2 in prosensory cells.
2022-11-04 | GSE180500 | GEO
Project description:Age-related hearing loss is a progressive sensorineural hearing loss that occurs as people get older. Degeneration of the organ of Corti and atrophy of the lateral wall of the scala media in the inner ear are the two primary causes. Transcriptome analysis has emerged as a powerful tool in revealing the genetic and molecular profile of a cell or a population of cells during aging in organism models, animals and humans. Comparison of transcriptomes between young and older animals have identified many common genes and pathways that are associated with aging and longevity. We used RNA-seq to examine changes in gene expression profiles of the stria vascularis between 9- and 26-month-old CBA mice. Our transcriptome analysis provides a rich resource for mechanistic studies of biological aging of stria vascularis.
2022-03-01 | GSE154833 | GEO
Project description:To understand the molecular control of development and regeneration in the mammalian cochlear sensory epithelia, we performed a comparative study of gene expression patterns between postnatal day-3 (P3) and adult stages using a microarrays approach. Two inner ear development stages were used in this study, Post-natal day three and eight-week-old adult. A total number of sixty Swiss mice were exploited for each stage. The cochlear sensory epithelia (CSE) were collected from the inner ears and immediately placed in RNA later solution. A total of six independent dissection experiments were carried out separately in order to obtain three biological replicates for each stage. In each experiment, the CSE from 20 mice were pooled. Total RNA was purified from each biological sample separately using RNAeasy Mini Kit and the RNA integrity was assessed by the Nanodrop 2000
2012-01-01 | E-GEOD-32963 | biostudies-arrayexpress
Project description:BackgroundDisturbance of acid-base balance in the inner ear is known to be associated with hearing loss in a number of conditions including genetic mutations and pharmacologic interventions. Several previous physiologic and immunohistochemical observations lead to proposals of the involvement of acid-base transporters in stria vascularis.ResultsWe directly measured acid flux in vitro from the apical side of isolated stria vascularis from adult C57Bl/6 mice with a novel constant-perfusion pH-selective self-referencing probe. Acid efflux that depended on metabolism and ion transport was observed from the apical side of stria vascularis. The acid flux was decreased to about 40 % of control by removal of the metabolic substrate (glucose-free) and by inhibition of the sodium pump (ouabain). The flux was also decreased a) by inhibition of Na,H-exchangers by amiloride, dimethylamiloride (DMA), S3226 and Hoe694, b) by inhibition of Na,2Cl,K-cotransporter (NKCC1) by bumetanide, and c) by the likely inhibition of HCO3/anion exchange by DIDS. By contrast, the acid flux was increased by inhibition of gastric H,K-ATPase (SCH28080) but was not affected by an inhibitor of vH-ATPase (bafilomycin). K flux from stria vascularis was reduced less than 5 % by SCH28080.ConclusionsThese observations suggest that stria vascularis may be an important site of control of cochlear acid-base balance and demonstrate a functional role of several acid-base transporters in stria vascularis, including basolateral H,K-ATPase and apical Na,H-exchange. Previous suggestions that H secretion is mediated by an apical vH-ATPase and that basolateral H,K-ATPase contributes importantly to K secretion in stria vascularis are not supported. These results advance our understanding of inner ear acid-base balance and provide a stronger basis to interpret the etiology of genetic and pharmacologic cochlear dysfunctions that are influenced by endolymphatic pH.
| S-EPMC4982335 | biostudies-literature
Project description:Sensorineural hearing loss (SNHL) is one of the most common congenital disorders in humans, afflicting one in every thousand newborns. The majority is of heritable origin and can be divided in syndromic and nonsyndromic forms. Knowledge of the expression profile of affected genes in the human fetal cochlea is limited, and as many of the gene mutations causing SNHL likely affect the stria vascularis or cochlear potassium homeostasis (both essential to hearing), a better insight into the embryological development of this organ is needed to understand SNHL etiologies. We present an investigation on the development of the stria vascularis in the human fetal cochlea between 9 and 18 weeks of gestation (W9-W18) and show the cochlear expression dynamics of key potassium-regulating proteins. At W12, MITF+/SOX10+/KIT+ neural-crest-derived melanocytes migrated into the cochlea and penetrated the basement membrane of the lateral wall epithelium, developing into the intermediate cells of the stria vascularis. These melanocytes tightly integrated with Na+/K+-ATPase-positive marginal cells, which started to express KCNQ1 in their apical membrane at W16. At W18, KCNJ10 and gap junction proteins GJB2/CX26 and GJB6/CX30 were expressed in the cells in the outer sulcus, but not in the spiral ligament. Finally, we investigated GJA1/CX43 and GJE1/CX23 expression, and suggest that GJE1 presents a potential new SNHL associated locus. Our study helps to better understand human cochlear development, provides more insight into multiple forms of hereditary SNHL, and suggests that human hearing does not commence before the third trimester of pregnancy.
| S-EPMC5024031 | biostudies-literature