MiR-96 regulates the functional maturation of mammalian cochlear hair cells

MicroRNAs (miRNAs) are small non-coding RNAs able to regulate a broad range of protein-coding genes involved in many biological processes by decreasing the level of target mRNA in mammals (Guo et al 2010 Nature 466:835- 40). MiR-96 is a sensory organ-specific miRNA (Xu et al 2007 J Biol Chem 282:25053-66) which is present during development in hair cells and auditory spiral ganglion neurons of the mouse cochlea (Sacheli et al 2009 Gene Exp Pattern 9:364-370). In humans, mutations in miR-96 cause non-syndromic progressive hearing loss (Mencía et al 2009 Nat Gen 41:609-13). The mouse mutant diminuendo has a single base change in the seed region of the Mir96 gene leading to deafness and widespread changes in the expression of many genes (Lewis et al 2009 Nat Gen 41:614-18). We investigated the effect of this mutant miR-96 on the functional maturation of hair cells using whole-cell patch clamp recordings in diminuendo mice. We found that in the absence of wildtype miR-96, the biophysical properties of hair cells do not develop leading to an embryonic/early postnatal-like expression and shape of voltage-gated potassium and calcium currents, spiking responses and calcium sensitivity of exocytosis. Moreover, maturation of the stereocilia bundle of hair cells and the remodelling of auditory nerve connections within the cochlea fail to occur in miR-96 mutants. We conclude that miR-96 is a major coordinator of the physiological maturation of mammalian hair cells and thus regulates one of the most dist inctive functional refinements of the mammalian auditory system.