Overexpression of ROM-1 in the Cone-Dominant Retina

Chakraborty, Dibyendu; Conley, Shannon M.; Nash, Zack; Ding, Xi‐Qin; Naash, Muna I.

doi:10.1007/978-1-4614-0631-0_80

Cited by 6 publications

(8 citation statements)

References 17 publications

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“…Interestingly, taurine, a known cysteine derivative, is transported by Slc6a6 into photoreceptors to enhance the expression of many essential genes (15); however, overexpression of two essential genes, Cngb1 and Rom1, has been reported to result in attenuated scotopic ERG and photopic ERG responses, respectively (25,26). We found that the persistent expression of Slc6a6 resulted in an up-regulation of Cngb1 and Rom1, which may explain the attenuated ERG responses (Fig.…”

Section: Discussionmentioning

confidence: 76%

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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: Discussionmentioning

confidence: 76%

“…Previous studies have found that the overexpression of essential genes, such as Cngb1, Rom1, and Rho (25)(26)(27), can be detrimental to photoreceptors. We hypothesized that the overexpression of Slc6a6 is harmful to photoreceptors by the activation of essential genes.…”

Section: Overexpression Of Slc6a6 Is Detrimental To Mouse Photoreceptmentioning

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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“…The role of Rom1 in these differences is less well understood; in large part because overall changes in the absence of Rom1 are less severe (11) and because fewer studies have evaluated the role of Rom1 in the retina. We have shown that cone cells overexpressing a Rom1 transgene have structural and functional defects, suggesting that excess Rom1 can be toxic in cones (35), but it is not clear whether this would be the case in rods. Eliminating Rom1 leads to alterations in disc sizing (11) and it is possible that the role of Rom1 in disc sizing/alignment is different in rods vs. cones.…”

Section: Discussionmentioning

confidence: 98%

Rom1 converts Y141C-Prph2-associated pattern dystrophy to retinitis pigmentosa

Conley¹,

Stuck²,

Watson³

et al. 2017

Hum. Mol. Genet.

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Mutations in peripherin 2 (PRPH2), also known as retinal degeneration slow/RDS, lead to various retinal degenerations including retinitis pigmentosa (RP) and macular/pattern dystrophy (MD/PD). PRPH2-associated disease is often characterized by a phenotypic variability even within families carrying the same mutation, raising interest in potential modifiers. PRPH2 oligomerizes with its homologue rod outer segment (OS) membrane protein 1 (ROM1), and non-pathogenic PRPH2/ROM1 mutations, when present together, lead to digenic RP. We asked whether ROM1 could modify the phenotype of a PRPH2 mutation associated with a high degree of intrafamilial phenotypic heterogeneity: Y141C. In vitro, Y141C-Prph2 showed signs of retention in the endoplasmic reticulum (ER), however co-expression with Rom1 rescued this phenotype. In the heterozygous Y141C knockin mouse model (Prph2Y/+), Y141C-Prph2 and Rom1 formed abnormal complexes but were present at normal levels. Abnormal complexes were eliminated in the absence of Rom1 (Prph2Y/+/Rom1-/-) and total Prph2 levels were reduced to those found in the haploinsufficient Prph2+/- RP model. The biochemical changes had functional and structural consequences; while Prph2Y/+ animals exhibited a cone-rod electroretinogram defect, Prph2Y/+/Rom1-/- animals displayed a rod-dominant phenotype and OSs similar to those seen in the Prph2+/-. These data show that ablation of Rom1 results in the conversion of an MD/PD phenotype characterized by cone functional defects and the formation of abnormal Prph2/Rom1 complexes to an RP phenotype characterized by rod-dominant functional defects and reductions in total Prph2 protein. Thus one method by which ROM1 may act as a disease modifier is by contributing to the large variability in PRPH2-associated disease phenotypes.

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“…However, the specifics of this model remain vague. When ROM-1 was over-expressed in the cone-dominant nrl −/− retina via transgenesis, the amount of PRPH2/RDS higher-order complexes was reduced and OS abnormalities were seen, suggesting that excess ROM-1 may be toxic to cells (Chakraborty et al, 2012). Taken together, these data suggest that though ROM-1 is not essential for OS formation, it does play an important role in fine tuning OS formation possibly through an intrinsic property of ROM-1 or by fine tuning the distribution of PRPH2/RDS complex types, and that the ratio of PRPH2/RDS to ROM-1 must be maintained (Clarke et al, 2000).…”

Section: Role Of Prph2/rds In the Photoreceptormentioning

confidence: 99%

PRPH2/RDS and ROM-1: Historical context, current views and future considerations

Stuck

Conley

Naash

2016

Progress in Retinal and Eye Research

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106

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Peripherin2 (PRPH2), also known as RDS (retinal degeneration slow) is a photoreceptor specific glycoprotein which is essential for normal photoreceptor health and vision. PRPH2/RDS is necessary for the proper formation of both rod and cone photoreceptor outer segments, the organelle specialized for visual transduction. When PRPH2/RDS is defective or absent, outer segments become disorganized or fail to form entirely and the photoreceptors subsequently degenerate. Multiple PRPH2/RDS disease-causing mutations have been found in humans, and they are associated with various blinding diseases of the retina such as macular degeneration and retinitis pigmentosa, the vast majority of which are inherited dominantly, though recessive LCA and digenic RP have also been associated with RDS mutations. Since its initial discovery, the scientific community has dedicated a considerable amount of effort to understanding the molecular function and disease mechanisms of PRPH2/RDS. This work has led to an understanding of how the PRPH2/RDS molecule assembles into complexes and functions as a necessary part of the machinery that forms new outer segment discs, as well as leading to fundamental discoveries about the mechanisms that underlie OS biogenesis. Here we discuss PRPH2/RDS-associated research and how experimental results have driven the understanding of the PRPH2/RDS protein and its role in human disease.

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Overexpression of ROM-1 in the Cone-Dominant Retina

Cited by 6 publications

References 17 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

Rom1 converts Y141C-Prph2-associated pattern dystrophy to retinitis pigmentosa

PRPH2/RDS and ROM-1: Historical context, current views and future considerations

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