miR-183/96 plays a pivotal regulatory role in mouse photoreceptor maturation and maintenance

MicroRNAs (miRNAs) are known to be essential for retinal maturation and functionality; however, the role of the most abundant miRNAs, the miR-183/96/182 cluster (miR-183 cluster), in photoreceptor cells remains unclear. Here we demonstrate that ablation of two components of the miR-183 cluster, miR-...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 114; no. 24; pp. 6376 - 6381
Main Authors Xiang, Lue, Chen, Xue-Jiao, Wu, Kun-Chao, Zhang, Chang-Jun, Zhou, Gao-Hui, Lv, Ji-Neng, Sun, Lan-Fang, Cheng, Fei-Fei, Cai, Xue-Bi, Jin, Zi-Bing
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 13.06.2017
Subjects
Age
Biological Sciences
Clusters
Dislocations
Electroretinograms
Electroretinography
Maintenance
Maturation
Mice
miRNA
Nuclei
Photoreception
Photoreceptors
Retina
Rodents
Viruses
taurine transporter
regulation
miR-183/96/182 cluster
degeneration
photoreceptor
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Summary:MicroRNAs (miRNAs) are known to be essential for retinal maturation and functionality; however, the role of the most abundant miRNAs, the miR-183/96/182 cluster (miR-183 cluster), in photoreceptor cells remains unclear. Here we demonstrate that ablation of two components of the miR-183 cluster, miR-183 and miR-96, significantly affects photoreceptor maturation and maintenance in mice. Morphologically, early-onset dislocated cone nuclei, shortened outer segments and thinned outer nuclear layers are observed in the miR-183/96 double-knockout (DKO) mice. Abnormal photoreceptor responses, including abolished photopic electroretinography (ERG) responses and compromised scotopic ERG responses, reflect the functional changes in the degenerated retina. We further identify Slc6a6 as the cotarget of miR-183 and miR-96. The expression level of Slc6a6 is significantly higher in the DKO mice than in the wild-type mice. In contrast, Slc6a6 is down-regulated by adeno-associated virus-mediated overexpression of either miR-183 or miR-96 in wild-type mice. Remarkably, both silencing and overexpression of Slc6a6 in the retina are detrimental to the electrophysiological activity of the photoreceptors in response to dim light stimuli. We demonstrate that miR-183/96–mediated fine-tuning of Slc6a6 expression is indispensable for photoreceptor maturation and maintenance, thereby providing insight into the epigenetic regulation of photoreceptors in mice.
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Edited by Jeremy Nathans, Johns Hopkins University, Baltimore, MD, and approved April 26, 2017 (received for review November 22, 2016)
1L.X. and X.-J.C. contributed equally to this work.
Author contributions: L.X. and Z.-B.J. designed research; L.X., X.-J.C., K.-C.W., C.-J.Z., G.-H.Z., J.-N.L., L.-F.S., F.-F.C., and X.-B.C. performed research; X.-J.C., C.-J.Z., G.-H.Z., and F.-F.C. analyzed data; and L.X. and Z.-B.J. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1618757114