MicroRNA-183 Family Members Regulate Sensorineural Fates in the Inner Ear

Abstract

Members of the microRNA (miRNA) 183 family (miR-183, miR-96, and miR-182) are expressed abundantly in specific sensory cell types in the eye, nose, and inner ear. In the inner ear, expression is robust in the mechanosensory hair cells and weak in the associated statoacoustic ganglion (SAG) neurons; both cell types can share a common lineage during development. Recently, dominant-progressive hearing loss in humans and mice was linked to mutations in the seed region of miR-96, with associated defects in both development and maintenance of hair cells in the mutant mice. To understand how the entire triplet functions in the development of mechanosensory hair cells and neurons of the inner ear, we manipulated the levels of these miRNAs in zebrafish embryos using synthesized miRNAs and antisense morpholino oligonucleotides (MOs). Overexpression of miR-96 or miR-182 induces duplicated otocysts, ectopic or expanded sensory patches, and extra hair cells, whereas morphogenesis of the SAG is adversely affected to different degrees. In contrast, knockdown of miR-183, miR-96, and miR-182 causes reduced numbers of hair cells in the inner ear, smaller SAGs, defects in semicircular canals, and abnormal neuromasts on the posterior lateral line. However, the prosensory region of the posterior macula, where the number of hair cells is reduced by ϳ50%, is not significantly impaired. Our findings suggest both distinct and common roles for the three miRNAs in cell-fate determination in the inner ear, and these principles might apply to development of other sensory organs.

Improving hearing loss gene testing: a systematic review of gene evidence toward more efficient next-generation sequencing–based diagnostic testing and interpretation

“…10 The study lacked segregation or functional data to support pathogenicity of any of the variants identified, failing to support a gene-disease association between MYO1A and 25 and they are thought to regulate sensorineural cell fates in the inner ear. 26 Although three variants in the MIR96 gene have been shown to segregate with disease in three families with autosomaldominant nonsyndromic hearing loss, 27,28 no variants were identified in either MIR182 or MIR183 in patients with hearing loss. A mouse model strongly supports the contribution of MIR96 to hearing loss, 29 though no such evidence has been found for MIR182 and MIR183; their expression as part of a polycistronic transcript in the inner ear is insufficient to assume a functional role for these microRNAs in the auditory process.…”

miR-182 is a negative regulator of osteoblast proliferation, differentiation, and skeletogenesis through targeting FoxO1

“…6D). (24) In alizarin red staining of whole zebrafish embryos injected with control-miR (Fig. 6A') or miR-182 (Fig.…”

miR-96 regulates the progression of differentiation in mammalian cochlear inner and outer hair cells

“…Members of the miR-183 family (miR-96, miR-182, and miR-183) are specific to sensory organs (17,18) and are highly expressed in the inner ear (19,20), eye (17), and nose (21). In the inner ear, they appear to be important for determining cell fate and development (22). miR-96 is expressed in developing cochlear hair cells up to at least P5 (23) and in the spiral ganglion up to P14 (19).…”