Abstract
ABSTRACTThe microRNA miR-96 is important for hearing, as point mutations in humans and mice result in dominant progressive hearing loss. Mir96 is expressed in sensory cells along with Mir182 and Mir183, but the roles of these closely-linked microRNAs are as yet unknown. Here, we analyse mice carrying null alleles of Mir182, and of Mir183 and Mir96 together to investigate their roles in hearing. We found that Mir183/96 heterozygous mice had normal hearing and homozygotes were completely deaf with abnormal hair cell stereocilia bundles and reduced numbers of inner hair cell synapses at 4 weeks of age. Mir182 knockout mice developed normal hearing then exhibited progressive hearing loss. Our transcriptional analyses revealed significant changes in a range of other genes, but surprisingly there were fewer genes with altered expression in the organ of Corti of Mir183/96 null mice compared with our previous findings in Mir96Dmdo mutants, which have a point mutation in the miR-96 seed region. This suggests that the more-severe phenotype of Mir96Dmdo mutants compared with Mir183/96 mutants, including progressive hearing loss in Mir96Dmdo heterozygotes, is likely to be mediated by the gain of novel target genes in addition to the loss of its normal targets. We propose three mechanisms of action of mutant miRNAs: loss of targets that are normally completely repressed, loss of targets for which transcription is normally buffered by the miRNA, and gain of novel targets. Any of these mechanisms could lead to a partial loss of a robust cellular identity and consequent dysfunction.
Highlights
The microRNAs miR-96, miR-182 and miR-183 are expressed together on a single transcript in sensory cells, including the retina and the hair cells of the inner ear (Weston et al, 2006; Xu et al, 2007)
Mir183/96dko mice have a less-severe phenotype than Mir96Dmdo mice Mice heterozygous for the Mir96Dmdo point mutation exhibit earlyonset rapidly progressive hearing loss; even at P15 they have very raised thresholds (Kuhn et al, 2011)
We initially concluded that this was more likely to be due to haploinsufficiency than to the gain of novel targets, because humans heterozygous for different point mutations had progressive hearing loss (Mencia et al, 2009)
Summary
The microRNAs (miRNAs) miR-96, miR-182 and miR-183 are expressed together on a single transcript in sensory cells, including the retina and the hair cells of the inner ear (Weston et al, 2006; Xu et al, 2007). In homozygous Mir96Dmdo mice, most of the cochlear hair cells die by 28 days after. Justice Received 7 September 2020; Accepted 3 December 2020 birth This is not the cause of the hearing loss; even before the onset of normal hearing, homozygote hair cells fail to mature both morphologically and physiologically, remaining in their immature state, and heterozygote hair cells show a developmental delay. The complete loss of all mature miRNAs from the inner ear results in early developmental defects including a severely truncated cochlear duct (Friedman et al, 2009; Soukup et al, 2009). The complete loss of all mature miRNAs from the inner ear results in early developmental defects including a severely truncated cochlear duct (Friedman et al, 2009; Soukup et al, 2009). miR-96, miR-182 and miR-183 have been implicated in other diseases, including glaucoma (Liu et al, 2016), ischemic injury (Cui and Yang, 2013; Duan et al, 2019) and spinal cord injury (Ling et al, 2017)
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