Abstract
Hearing loss caused by environmental and genetic factors is exacerbated by the inability of mammalian auditory hair cells to spontaneously regenerate. Recent studies demonstrate that mechanosensitive hair cells can be derived from embryonic or induced pluripotent stem cells, and that Atoh1 can induce ectopic hair cells in the embryonic mouse inner ear. These studies suggest important guidance strategies for regenerating hair cells that might be used in non-immunogenic therapies, but the efficacy of other factors in effecting hair cell fate remains to be elucidated. We have previously shown the conservation and specific expression of microRNA-183 family members amongst vertebrate hair cells, and that microRNAs are necessary for the differentiation and maintenance of hair cells in the mouse inner ear. We investigated the ability of hair cell microRNAs in conjunction with Atoh1 to influence gene expression profiles in presumptive prosensory precursor cells derived from the embryonic mouse otocyst. Microarray analyses of cells transfected with plasmids expressing Atoh1 and/or hair cell microRNAs exhibit mild changes in gene expression consistent with the function of microRNAs. Nevertheless, results indicate that the miR-183 family can specifically affect the downregulation of certain genes associated with alternative cell fate. We validated Notch1 and the Atoh1 antagonists Sox2 and Hes1 as miR-183 family member targets. The data suggest that the miR-183 family regulates expression of key factors involved in lineage specification in the inner ear and suggest that microRNAs might be useful factors in guidance strategies for hair cell regeneration.