Genomic non-redundancy of the mir-183/96/182 cluster and its requirement for hair cell maintenance

Abstract

microRNAs are important regulators of gene expression. In the retina, the mir-183/96/182 cluster is of particular interest due to its robust expression and studies in which loss of the cluster caused photoreceptor degeneration. However, it is unclear which of the three miRNAs in the cluster are ultimately required in photoreceptors, whether each may have independent, contributory roles, or whether a single miRNA from the cluster compensates for the loss of another. These are important questions that will not only help us to understand the role of these particular miRNAs in the retina, but will deepen our understanding of how clustered microRNAs evolve and operate. To that end, we have developed a complete panel of single, double, and triple mir-183/96/182 mutant zebrafish. While the retinas of all mutant animals were normal, the triple mutants exhibited acute hair cell degeneration which corresponded with impaired swimming and death at a young age. By measuring the penetrance of this phenotype in each mutant line, we determine which of the three miRNAs in the cluster are necessary and/or sufficient to ensure normal hair cell development and function.

Characterising the Transcriptional and Translational Impact of the Schizophrenia-Associated miR-1271-5p in Neuronal Cells

“…Specifically, homozygous knockout of miR-182 in the mouse retina has previously been reported to induce no discernible phenotype, which suggests miR-96 and miR-183 compensate for miR-182 loss [60]. Likewise, while miR-96/182/183 CRISPR/Cas9 mutants compromised zebrafish hair cells, individual and combined miR-96/183 and miR-183/182 mutants had a limited effect, which further suggests functional redundancy among these miRNAs [61]. It would, therefore, be interesting to determine whether this redundancy extends to miR-1271-5p, considering the miR-196/183/182 cluster is involved in hippocampal long-term memory [54], pain sensitivity [56,62], retinal cell function [60], and hair cell maintenance [61], while dysregulation has been identified in a range of neurological and psychiatric disorders [59].…”

MicroRNA Signatures of the Developing Primate Fovea

“…For example, miR-183, miR-96, and miR-182 are significantly enriched in the developing fovea (3.3-fold, 5.21-fold, and 5.11-fold, respectively). miR-183/-96/-182 are co-expressed together as a single primary transcript, are highly expressed in developing photoreceptors in mouse and zebrafish, and play essential roles in photoreceptor development and maintenance ( Zhu et al, 2011 ; Xiang et al, 2017 ; Fogerty et al, 2019 ). Since the temporal region of the developing primate eye exhibits both a developmental acceleration and higher percentage of photoreceptors, it is not surprising that this family is expressed at greater levels in the temporal samples.…”

Sophisticated Gene Regulation for a Complex Physiological System: The Role of Non-coding RNAs in Photoreceptor Cells

“…Additionally, miR-182-depleted mice showed a thinner IS/OS layer, a progressive reduction of scotopic and photopic ERG responses and increased sensitivity to light-damage compared to control littermates (Wu et al, 2019 ). In contrast, a study assessing the potential redundancy of the cluster members reported the absence of retinal defects in single, double, and triple mir-183/96/182 mutant zebrafish (Fogerty et al, 2019 ).…”