Abstract
MicroRNAs are small non-coding RNAs that are processed through an endogenous biological pathway and function to post-transcriptionally regulate target gene expression. MicroRNAs affect cellular proliferation, differentiation, and morphogenesis in development and also have been found to play a role in many disease states. We hypothesize that microRNAs are essential for hair cell development. To test this hypothesis, we analyzed which microRNAs were present in the mouse inner ear, investigated the evolutionary conservation of a hair cell specific microRNA family, and utilized a conditional Dicer knockout mouse model to determine the role of microRNAs in the development of inner ear hair cells. Our results demonstrate that approximately one-fourth of known microRNAs are expressed in the mouse inner ear, often persisting into adulthood, with certain microRNAs exhibiting cell-specific expression patterns, suggesting that they contribute to the development and function of the mouse inner ear. Furthermore, highly-conserved microRNA-183 orthologs exist in both deuterostomes and protostomes where they are predominantly expressed in vertebrate sensory hair cells, innervated regions of vertebrate deuterostomes, and in sensilla of Drosophila and C. elegans. Thus, expression of microRNA-183 family is conserved in possibly homologous but morphologically distinct cells and organs. These results suggest that microRNA-183 family members contribute specifically to neurosensory development or function, and that extant metazoan sensory organs are derived from cells that share genetic programs of common evolutionary origin. In the conditional Dicer knockout mouse, otocyst-derived ganglia exhibit rapid neuron-specific miR-124 depletion by E11.5 and profound defects in subsequent sensory epithelial innervation. However, the small and malformed inner ear at E17.5 exhibits residual and graded hair cell-specific miR-183 expression in the three remaining sensory epithelia (posterior crista, utricle, and cochlea) that closely corresponds to the degree of hair cell and sensory epithelium differentiation, and Fgf10 expression required for morphohistogenesis. The correlation of differential and delayed depletion of mature miRNAs with the derailment of inner ear development demonstrates that miRNAs are crucial for inner ear neurosensory development and neurosensory-dependent morphogenesis. Understanding microRNA functions in hair celldevelopment of the mouse inner ear potentiates the innovation of clinically relevant therapeutics for treating hearing loss and balance disorders.