Abstract
The microRNA (miR)-183/96/182 cluster plays important roles in the development and functions of sensory organs, including the inner ear. Point-mutations in the seed sequence of miR-96 result in non-syndromic hearing loss in both mice and humans. However, the lack of a functionally null mutant has hampered the evaluation of the cluster’s physiological functions. Here we have characterized a loss-of-function mutant mouse model (miR-183CGT/GT), in which the miR-183/96/182 cluster gene is inactivated by a gene-trap (GT) construct. The homozygous mutant mice show profound congenital hearing loss with severe defects in cochlear hair cell (HC) maturation, alignment, hair bundle formation and the checkboard-like pattern of the cochlear sensory epithelia. The stereociliary bundles retain an immature appearance throughout the cochlea at postnatal day (P) 3 and degenerate soon after. The organ of Corti of mutant newborn mice has no functional mechanoelectrical transduction. Several predicted target genes of the miR-183/96/182 cluster that are known to play important roles in HC development and function, including Clic5, Rdx, Ezr, Rac1, Myo1c, Pvrl3 and Sox2, are upregulated in the cochlea. These results suggest that the miR-183/96/182 cluster is essential for stereociliary bundle formation, morphogenesis and function of the cochlear HCs.
Highlights
The miR-183/96/182 cluster was originally identified as a sensory organ-specific miRNA cluster[5,7,15,16,17]
These data suggest that inactivation of the miR-183/96/182 cluster in the cochlea resulted in profound hearing loss
FM1–43, a fluorescent dye that enters through functional Mechanoelectrical transduction (MET) channels[29], failed to load in the hair cell (HC) of cochlear organotypic cultures derived from P1 KO mice (Fig. 5b), whilst dye uptake was evident as bright fluorescence in the HCs of WT organotypic cultures (Fig. 5a)
Summary
The miR-183/96/182 cluster was originally identified as a sensory organ-specific miRNA cluster[5,7,15,16,17]. Further examination has shown that one of the point mutations causes arrest of HC development and maturation[23] These data suggest that miR-96 plays a predominant role among members of the miR-183/96/182 cluster in inner ear function. We showed that inactivation of the cluster results in syndromic retinal dystrophy with multisensory defects including a circling phenotype, typical of vestibular defect[17]. This result suggests that loss of function of the miR-183/96/182 cluster leads to significant functional defects of the inner ear. Our results demonstrate that loss of function of the miR183/96/182 cluster causes severe defects in HC differentiation, morphogenesis and function, leading to profound congenital syndromic deafness in mice
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