Inactivation of the microRNA<i>-183/96/182</i>cluster results in syndromic retinal degeneration

Lumayag, Stephen; Haldin, Caroline E.; Corbett, Nicola J.; Wahlin, Karl; Cowan, Colleen; Turturro, Sanja; Larsen, Peter E.; Kovacs, Beatrix; Witmer, P. Dane; Valle, David; Zack, Donald J.; Nicholson, Daniel A.; Xu, Shunbin

doi:10.1073/pnas.1212655110

Cited by 174 publications

(260 citation statements)

References 109 publications

(117 reference statements)

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“…Previous studies have reported that the down-regulation of expression of the miR-183 cluster in different models can lead to retinal degeneration (4)(5)(6). Although the retinal degeneration observed in our DKO mice was similar to that reported in previous models, the defects in the cones were distinct from those observed in other studies.…”

Section: Discussionsupporting

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

Xiang

Chen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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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 adenoassociated 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.miR-183/96/182 cluster | regulation | photoreceptor | taurine transporter | degeneration M icroRNAs (miRNAs) are known to act as important epigenetic coordinators during posttranscriptional processing via the regulation of hundreds of target genes with great temporal and spatial precision (1-3). Wholesale and individual disruption of miRNAs has been shown to result in various retinal defects and other sensorial diseases (4-6). The retinal photoreceptor is a type of ciliated neuron in which the miR-183 cluster represents the most highly expressed miRNAs. Although different mouse models have been generated to determine the roles of the miR-183 cluster, many previous studies have used nonspecific or incomplete miRNA depletion to examine the effects of eliminating specific miRNAs on photoreceptor degeneration (5, 6). Little is known about the impact of a "null" miR-183/96/182 model in vivo.A recent study of miR-182 and miR-183 identified these two miRNAs as essential for the maturation and function of cone photoreceptors (7). In addition, their expression is necessary and sufficient for the formation of cone outer segments (OSs) (7). Another study likewise showed that inactivation of the miR-183 cluster by gene trapping resulted in abnormal electroretinography (ERG) responses, progressive synaptic defects, and progressive retinal degeneration (4). Other investigators have reported that impairment of miR-96 resulted in hair cell death in the inner ear, as well as progressive hearing loss in zebrafish, mice, and humans (8-10). Notwithstanding these findings, however, our understanding of the re...

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Section: Discussionsupporting

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“…Wholesale and individual disruption of miRNAs has been shown to result in various retinal defects and other sensorial diseases (4)(5)(6). The retinal photoreceptor is a type of ciliated neuron in which the miR-183 cluster represents the most highly expressed miRNAs.…”

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confidence: 99%

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

Xiang

Chen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…This is also the first example to our knowledge of a microRNA mutation with a causative role in inherited retinal dystrophies in patients, as to date, microRNAs have been linked to such diseases only in mouse (45).…”

Section: Discussionmentioning

confidence: 99%

MiR-204 is responsible for inherited retinal dystrophy associated with ocular coloboma

Conte

Hadfield

Barbato

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

111

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Ocular developmental disorders, including the group classified as microphthalmia, anophthalmia, and coloboma (MAC) and inherited retinal dystrophies, collectively represent leading causes of hereditary blindness. Characterized by extreme genetic and clinical heterogeneity, the separate groups share many common genetic causes, in particular relating to pathways controlling retinal and retinal pigment epithelial maintenance. To understand these shared pathways and delineate the overlap between these groups, we investigated the genetic cause of an autosomal dominantly inherited condition of retinal dystrophy and bilateral coloboma, present in varying degrees in a large, five-generation family. By linkage analysis and exome sequencing, we identified a previously undescribed heterozygous mutation, n.37C > T, in the seed region of microRNA-204 (miR-204), which segregates with the disease in all affected individuals. We demonstrated that this mutation determines significant alterations of miR-204 targeting capabilities via in vitro assays, including transcriptome analysis. In vivo injection, in medaka fish (Oryzias latipes), of the mutated miR-204 caused a phenotype consistent with that observed in the family, including photoreceptor alterations with reduced numbers of both cones and rods as a result of increased apoptosis, thereby confirming the pathogenic effect of the n.37C > T mutation. Finally, knockdown assays in medaka fish demonstrated that miR-204 is necessary for normal photoreceptor function. Overall, these data highlight the importance of miR-204 in the regulation of ocular development and maintenance and provide the first evidence, to our knowledge, of its contribution to eye disease, likely through a gain-of-function mechanism.

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“…miR-96 was found to be overexpressed in many types of cancer and to promote cancer cell proliferation, metastasis, and metabolism (Guo et al, 2014;Yu et al, 2014;Zhang et al, 2014). In addition, miR-96, together with miR-182 and miR-183, are highly expressed in the retina and are associated with syndromic retinal degeneration (Lumayag et al, 2013). Moreover, a mutation in the seed region of miR-96 can result in progressive hearing loss (Lewis et al, 2009;Mencia et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

miR-96 inhibits cardiac hypertrophy by targeting growth factor receptor-bound 2

et al. 2015

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ABSTRACT. Increasing evidence has indicated that microRNAs are involved in the pathogenesis of cardiac hypertrophy. However, whether miR-96 is involved in heart diseases, particularly cardiac hypertrophy, remains unclear. In this study, we found that miR-96 is a negative regulator of cardiac hypertrophy. In primary cardiomyocytes, overexpression of miR-96 inhibited phenylephrine-induced cardiomyocyte hypertrophy and decreased the mRNA expression of cardiac hypertrophy markers such as atrial natriuretic factor and β-myosin heavy chain. Interestingly, we found that growth factor receptor-bound 2 is a direct target of miR-96, which is a negative regulator of cardiac hypertrophy. Overexpression of miR-96 in cardiomyocytes led to reduced growth factor receptor-bound 2 expression. More importantly, miR-96 repressed the extracellular-regulated protein kinase signaling pathway by targeting growth factor receptor-bound 2 in cardiomyocytes. Our data demonstrate that miR-96 is a negative regulator of cardiac hypertrophy and extracellular-regulated protein kinase signaling, thus offering a new therapeutic strategy for cardiac hypertrophy.

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Inactivation of the microRNA-183/96/182cluster results in syndromic retinal degeneration

Cited by 174 publications

References 109 publications

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

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

MiR-204 is responsible for inherited retinal dystrophy associated with ocular coloboma

miR-96 inhibits cardiac hypertrophy by targeting growth factor receptor-bound 2

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