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A Cell Type-Specific Approach to Elucidate the Role of miR-96 in Inner Ear Hair Cells

ABSTRACT: Mutations in miRNA-96, a microRNA expressed within the hair cells (HCs) of the inner ear, result in progressive hearing loss in both mouse models and humans. While previous studies have delved into miR-96 transcriptional cascades via whole organ of Corti microarray experiments of diminuendo (Mir96Dmdo) mice, they face limitations in pinpointing cell type-specific differentially expressed genes. This hinders the ability to conclusively determine if the effects of Mir96Dmdo are specifically within HCs and contribute to the observed abnormal Mir96Dmdo HC phenotype and determine the role of miR-96 in HCs. In this study, we generate the first HC-specific RNA-sequencing (RNA-seq) datasets from Mir96Dmdo; Atoh1/nGFP+ postnatal day 1 wildtype, heterozygous, and homozygous mutant mice. Our differential gene expression analysis between Mir96Dmdo homozygous mutant HCs compared to wildtype HCs identified 215 upregulated and 428 downregulated genes. Many significantly downregulated genes in Mir96Dmdo homozygous mutant HCs have established roles in HC development and/or known roles in deafness such as Myo15, Myo7a, Ush1c Gfi1, and Ptprq, some of which were not previously identified in other miR-96 datasets. In addition, active modules of protein-protein interaction networks of significantly downregulated genes in Mir96Dmdo homozygous mutant HCs reveal enrichment in GO terms with biological functions such as sound perception and endocytosis. Genes significantly upregulated in Mir96Dmdo homozygous mutant HCs, which are more likely to be direct targets of miR-96, show higher expression in wildtype supporting cells compared to wildtype HCs, suggesting a role of miR-96 in suppressing non-HC genes during HC development. Finally, all generated HC-specific Mir96Dmdo RNA-seq datasets from this manuscript are now publicly available in the miR-96 specific gEAR profile (https://umgear.org/p?l=miR96).

ORGANISM(S): Mus musculus

PROVIDER: GSE255796 | GEO | 2024/05/09

REPOSITORIES: GEO

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Project description:Background: Dementia is one of the most common diseases in elderly people and hundreds of thousand new cases per year of Alzheimer’s disease (AD) are estimated. While the recent decade has seen significant advances in the development of novel biomarkers to identify dementias at their early stage, a great effort has been recently made to identify biomarkers able to improve differential diagnosis. However, only few potential candidates, mainly detectable in cerebrospinal fluid (CSF), have been described so far. Methods: We searched for miRNAs regulating MAPT translation. We employed a capture technology able to find the miRNAs directly bound to the MAPT transcript in cell lines. Afterwards, we evaluated the levels of these miRNAs in plasma samples from FTD (n = 42) and AD patients (n = 33) and relative healthy controls (HCs) (n = 42) by using qRT-PCR. Results: Firstly, we found all miRNAs that interact with the MAPT transcript. Ten miRNAs have been selected to verify their effect on Tau levels increasing or reducing miRNA levels by using cell transfections with plasmids expressing the miRNAs genes or LNA antagomiRs. Following the results obtained, miR-92a-3p, miR-320a and miR-320b were selected to analyse their levels in plasma samples of patients with FTD and AD respect to HCs. The analysis showed that the miR-92a-1-3p was under-expressed in both AD and FTD compared to HCs. Moreover, miR-320a was upregulated in FTD vs. AD patients, particularly in men when we stratified by sex. Respect to HC, the only difference is showed in men with AD who have reduced levels of this miRNA. Instead, miR-320b is up-regulated in both dementias, but only patients with FTD maintain this trend in both genders. Conclusions: Our results seem to identify miR-92a-3p and miR-320a as possible good biomarkers to discriminate AD from HC, while miR-320b to discriminate FTD from HC, particularly in males. Combining three miRNAs improves the accuracy only in females, particularly for differential diagnosis (FTD vs. AD) and to distinguish FTD from HC.

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A Cell Type-Specific Approach to Elucidate the Role of miR-96 in Inner Ear Hair Cells

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