The microRNA miR-96 is important for hearing, as point mutations in humans and mice result in dominant progressive hearing loss. Mir96 is expressed in sensory cells along with Mir182 and Mir183, but the roles of these closely-linked microRNAs are as yet unknown. Here we analyse mice carrying null alleles of Mir182, and of Mir183 and Mir96 together to investigate their roles in hearing. We found that Mir183/96 heterozygous mice had normal hearing and homozygotes were completely deaf with abnormal hair cell stereocilia bundles and reduced numbers of inner hair cell synapses at four weeks old. Mir182 knockout mice developed normal hearing then exhibited progressive hearing loss. Our transcriptional analyses revealed significant changes in a range of other genes, but surprisingly there were fewer genes with altered expression in the organ of Corti of Mir183/96 null mice compared with our previous findings in Mir96 ^Dmdo mutants, which have a point mutation in the miR-96 seed region. This suggests the more severe phenotype of Mir96 ^Dmdo mutants compared with Mir183/96 mutants, including progressive hearing loss in Mir96 ^Dmdo heterozygotes, is likely to be mediated by the gain of novel target genes in addition to the loss of its normal targets. We propose three mechanisms of action of mutant miRNAs; loss of targets that are normally completely repressed, loss of targets whose transcription is normally buffered by the miRNA, and gain of novel targets. Any of these mechanisms could lead to a partial loss of a robust cellular identity and consequent dysfunction.

中文翻译：

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Mir183/96/182 突变导致的听力损伤表明功能丧失和增强都有影响。


microRNA miR-96 对听力很重要，因为人类和小鼠的点突变会导致显性进行性听力损失。 Mir96与Mir182和Mir183一起在感觉细胞中表达，但这些紧密相连的 microRNA 的作用尚不清楚。在这里，我们分析了携带Mir182以及Mir183和Mir96无效等位基因的小鼠，以研究它们在听力中的作用。我们发现Mir183 / 96杂合子小鼠听力正常，而纯合子小鼠在 4 周龄时完全聋，毛细胞静纤毛束异常，内毛细胞突触数量减少。 Mir182基因敲除小鼠的听力正常，但随后表现出进行性听力损失。我们的转录分析揭示了一系列其他基因的显着变化，但令人惊讶的是，与我们之前在Mir96 ^Dmdo突变体中的发现相比， Mir183/96缺失小鼠的 Corti 器官中表达改变的基因较少，该突变体在miR-96 种子区。这表明，与Mir183 / 96突变体相比， Mir96 ^Dmdo突变体具有更严重的表型，包括Mir96 ^Dmdo杂合子中的进行性听力损失，这可能是由于除了正常靶标的丧失之外，新靶标基因的获得所介导的。我们提出了突变 miRNA 的三种作用机制；通常完全抑制的靶标的丢失、转录通常由 miRNA 缓冲的靶标的丢失以及新靶标的获得。 这些机制中的任何一种都可能导致强大的细胞身份的部分丧失以及随之而来的功能障碍。