Abstract
Hearing loss is the most prevalent sensory defect, and although hearing aids and cochlear implants can provide sensory input, no current therapeutic options exist for restoration of normal hearing. The microRNA-183 family (miR-183, miR-96, and miR-182) is highly conserved and coordinately expressed in neurosensory cells including hair cells (HCs) and sensory neurons in the inner ear, and mutations in miR-96 cause deafness in both mice and humans. To specifically investigate the effects of miR-183 family member loss-of-function, miR-183/96 and miR-182 knockout (KO) mice were assessed. Behavioral observations and evaluation of Preyer’s reflex were used to grossly assess hair cell function. Stereocilia defects and hair cell loss in mice ranging from birth (postnatal day zero; P0) to P180 were examined by immunofluorescence microscopy (IFM) detection of MyoVIIa, scanning electron microscopy (SEM), and phase contrast microscopy (PCM) of plastic embedded sections through the organ of Corti. Spiral ganglion innervation was evaluated by IFM detection for acetylated tubulin. Targetscan predicted target genes were compared to neonatal and adult hair cell transcriptomes, genes known to cause hereditary hearing loss, and miR-183 familly confirmed target genes in the literature to identify a relevant subset of genes for further evaluation. Here we show that miR-183/96 KO caused delayed stereocilia development, gross stereocilia disorganization, hair cell loss, innervation defects and deafness. Moreover, miR-183/96 heterozygous (HET) and miR-182 KO mice showed relatively subtle stereocilia defects and age-related loss of acoustic startle response. Arhgdia, Sox2 and Tes were co-expressed with miR-183 family members and mildly upregulated in miR-183/96 KO mice, suggesting such targets might play a role in the observed phenotype. Results demonstrate that miR-183 family loss-of-function (LOF) led to stereocilia defects, hair cell loss, and contributing to hearing deficits. The challenge remains to conclusively identify miR-183 family effects on target genes and pathways that support hair cell maintenance and function to provide insight to approaches for preventing hair cell loss.