Characterization of molecular changes associated with Mef2c hypofunction in the mouse auditory nerve
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE182857 | GEO | 2022/08/24
REPOSITORIES: GEO
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Project description:Characterization of molecular changes associated with Mef2c hypofunction in the mouse auditory nerve
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Project description:Spiral ganglion neurons (SGNs) and the associated components of the auditory nerve are primary carriers of auditory information from hair cells to the brain. Loss of SGNs occurs with many pathological conditions, resulting in permanent sensorineural hearing loss. Neural stem/progenitors (NSPs) have been well-characterized in several locations of adult brain and retina. However, it is unclear whether NSPs are present in the adult auditory nerve. Here we examined the self-renewal potential of the adult auditory nerve using ouabain application as a well-established mouse model of acute SGN injury. The observed increase in cell proliferation, alteration in enchromatin/heterochromatin ratio and down-regulation of histone deacetylase expression in glial cells suggest that the quiescent glial cells convert to an activated state after SGN degeneration. This was further confirmed by global gene expression analysis of injured auditory nerves, which showed up-regulation of numerous neurogenesis- and/or development-associated genes shortly after ouabain exposure. These genes include molecular markers commonly used for the identification of NSPs. Under a strict culture regimen, auditory nerve-derived cells of adult mouse ears gave rise to neurospheres, suggesting that multipotent NSPs are present in adult cochlear nerve. Neurosphere assays on Sox2 transgenic mice revealed that Sox2+ glial cells are the source for NSPs. Our data also showed that acute injury or hypoxia enhances neurosphere formation. Taken together, our study revealed that glial cells of adult cochlea exhibit several NSP characteristics, and hence these mature non-neuronal cells may be important targets for promoting self-repair of degenerative auditory nerves. Auditory nerves were removed from the temporal bones of adult CBA/CaJ mice, aged 8 to 12 weeks. Tissues were either collected and used directly as the tissue samples or dissociated and used for the cell culture samples. Dissociated auditory nerve cells were propagated and grown to full confluency (5-7 days), constituting the cultured cell samples. For neurosphere samples, growth medium was changed to neurosphere formation medium and the cells were cultured for an additional 12 days. All samples were prepared in triplicate (n=3).
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Project description:Age-related hearing loss (ARHL) is a progressive sensorineural hearing loss that occurs as people get older. As many as 35% to 50% of the population aged between 65 and 75 have ARHL. Although age-related changes in the central auditory system can contribute to hearing impairment, degeneration of the mechanosensitive hair cells in the cochlea is the prevalent cause of ARHL. The molecular mechanisms of hair cell aging are largely unknown. To provide a comprehensive dataset of age-related genes and pathways in hair cells, we individually collected inner and outer hair cells, the two types of sensory receptor cells in the cochlea, from 9- and 26-month-old CBA/J mice and performed cell type-specific transcriptomic analysis. Our analysis showed a significant reduction of the expression of genes related to hair cell structure and function such as Tmc1, Kcnq4, Kcnj13, Slc7a14, Slc17a8, Chrna9/Chrna10, and Slc26a5. Our hair cell-specific transcriptome analysis provides a rich resource for mechanistic studies of biological aging of cochlear hair cells.
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