RT Journal Article SR Electronic T1 Hearing impairment due to Mir183/96/182 mutations suggests both loss and gain of function effects JF bioRxiv FD Cold Spring Harbor Laboratory SP 579003 DO 10.1101/579003 A1 Morag A. Lewis A1 Francesca Di Domenico A1 Neil J. Ingham A1 Haydn M. Prosser A1 Karen P. Steel YR 2019 UL http://biorxiv.org/content/early/2019/11/19/579003.abstract AB 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. We developed a new bioinformatic tool for creating a causal network connecting transcriptional regulators to their misregulated genes using publicly available data (PoPCoRN) to aid analysis of RNAseq data from the two new mutants. 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 Mir96Dmdo mutants which have a point mutation in the miR-96 seed region. This suggests the more severe phenotype of Mir96Dmdo mutants compared with Mir183/96 mutants, including progressive hearing loss in Mir96Dmdo heterozygotes, is likely to be mediated by the gain of novel target genes in addition to the loss of its normal targets.