Microphthalmia-associated Transcription Factor (MITF) Promotes Differentiation of Human Retinal Pigment Epithelium (RPE) by Regulating microRNAs-204/211 Expression

Adijanto, Jeffrey; Castorino, John J.; Wang, Zixuan; Maminishkis, Arvydas; Grunwald, Gerald B.; Philp, Nancy J.

doi:10.1074/jbc.m112.354761

Cited by 89 publications

(85 citation statements)

References 56 publications

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“…S4). The decrease in Slc16a8 (−2.6 FC), which was recently found to be altered in AMD (Adijanto et al, 2012), and the increase in Ap1s3 (1.77 FC), which is involved in clathrin-mediated vesicular transport from the Golgi or endosome (Boehm and Bonifacino, 2002), were validated by QPCR conducted on Dicer1 mutant and control RPE cells (supplementary material Fig. S4).…”

Section: Failure Of Photoreceptor Os Formation and Retinal Degeneratimentioning

confidence: 78%

“…These miRNAs were chosen because they are known to be highly expressed in the RPE throughout development and adult life (Shaham et al, 2013;Wang et al, 2010). Furthermore, miR-204 has been implicated in the inhibition of factors involved in epithelial-to-mesenchymal transition (EMT) and has been shown to be required for epithelial integrity as well as for maintaining primary cultures of human RPE in a non-proliferative state (Adijanto et al, 2012). The reduction of both miR-204 and miR-211 was clearly evident from E14.5 in the Dicer1 loxP/loxP ;Dct-Cre RPE (Fig.…”

Section: Conditional Ablation Of Dicer1 From Rpe Cells As a Global Inmentioning

confidence: 99%

“…Among these targets, several were noted as important developmental regulators (Meis2) (Conte et al, 2010;Xu et al, 2002) as well as encoding proteins involved in RPE physiology, such as Slc16a8 (Adijanto et al, 2012). Slc16a8 is a member of a family of proton- coupled monocarboxylate transporters that mediate lactate transport across the cell membrane, and Slc16a8 is highly expressed in the RPE, required for visual function and associated with AMD (Daniele et al, 2008;Philp et al, 1998;Priya et al, 2012), and has been experimentally shown to be upregulated by miR-204 (Adijanto et al, 2012). Genes with as yet unknown functions in the RPE, such as Ap1s3, which encodes a subunit of adaptor protein complex, should also be considered when attempting to identify the underlying cause of the phenotype following miRNAs loss from the RPE, as this subunit was recently shown to play a role in the endosomal translocation of signaling components involved in inflammation in skin keratinocytes (Boehm and Bonifacino, 2002;Setta-Kaffetzi et al, 2014).…”

Section: Dicer1 Is Dispensable For Rpe Fate and Survival During Develmentioning

confidence: 99%

“…Genes with as yet unknown functions in the RPE, such as Ap1s3, which encodes a subunit of adaptor protein complex, should also be considered when attempting to identify the underlying cause of the phenotype following miRNAs loss from the RPE, as this subunit was recently shown to play a role in the endosomal translocation of signaling components involved in inflammation in skin keratinocytes (Boehm and Bonifacino, 2002;Setta-Kaffetzi et al, 2014). Previous studies conducted in cultured human RPE cells suggested that miR-204 is essential for the maintenance of RPE specification, as without miR-204 the cells lose their epithelial identity and undergo EMT (Adijanto et al, 2012). By contrast, it seems that in vivo EMT does not take place in the absence of miRNAs including miR-204.…”

Section: Dicer1 Is Dispensable For Rpe Fate and Survival During Develmentioning

confidence: 99%

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MicroRNAs of the RPE are essential for RPE differentiation and photoreceptor maturation

et al. 2015

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Dysfunction of the retinal pigmented epithelium (RPE) results in degeneration of photoreceptors and vision loss and is correlated with common blinding disorders in humans. Although many proteincoding genes are known to be expressed in RPE and are important for its development and maintenance, virtually nothing is known about the in vivo roles of non-coding transcripts. The expression patterns of microRNAs (miRNAs) have been analyzed in a variety of ocular tissues, and a few were implicated to play role in RPE based on studies in cell lines. Here, through RPE-specific conditional mutagenesis of Dicer1 or Dgcr8 in mice, the importance of miRNAs for RPE differentiation was uncovered. miRNAs were found to be dispensable for maintaining RPE fate and survival, and yet they are essential for the acquisition of important RPE properties such as the expression of genes involved in the visual cycle pathway, pigmentation and cell adhesion. Importantly, miRNAs of the RPE are required for maturation of adjacent photoreceptors, specifically for the morphogenesis of the outer segments. The alterations in the miRNA and mRNA profiles in the Dicer1-deficient RPE point to a key role of miR-204 in regulation of the RPE differentiation program in vivo and uncover the importance of additional novel RPE miRNAs. This study reveals the combined regulatory activity of miRNAs that is required for RPE differentiation and for the development of the adjacent neuroretina.

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Section: Failure Of Photoreceptor Os Formation and Retinal Degeneratimentioning

confidence: 78%

Section: Conditional Ablation Of Dicer1 From Rpe Cells As a Global Inmentioning

confidence: 99%

Section: Dicer1 Is Dispensable For Rpe Fate and Survival During Develmentioning

confidence: 99%

Section: Dicer1 Is Dispensable For Rpe Fate and Survival During Develmentioning

confidence: 99%

See 2 more Smart Citations

MicroRNAs of the RPE are essential for RPE differentiation and photoreceptor maturation

et al. 2015

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“…A large body of evidence indicates that miR-204 plays a crucial role in the differentiation and function of all of the ocular structures in which it is expressed. In vitro assays have shown that miR-204 may be involved in the correct differentiation and function of RPE cells (27,29,30). MiR-204 is also required for proper lens development (9,10).…”

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.

100

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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The effects of microRNAs in activating neovascularization pathways in diabetic retinopathy

Satari

Aghadavod

Mirhosseini

et al. 2018

J of Cellular Biochemistry

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Diabetic retinopathy (DR) is one of the major complications of diabetes mellitus that causes diabetic macular edema and visual loss. DR is categorized, based on the presence of vascular lesions and neovascularization, into non-proliferative and proliferative DR. Vascular changes in DR correlate with the cellular damage and pathological changes in the capillaries of blood-retinal barrier. Several cytokines have been involved in inducing neovascularization. These cytokines activate different signaling pathways which are mainly responsible for the complications of DR. Recently; microRNAs (miRNAs) have been introduced as the key factors in the regulation of the cytokine expression which plays a critical role in neovascularization of retinal cells. Some studies have demonstrated that changing levels of miRNAs have essential role in the pathophysiology of vascular changes in patients with DR. The aim of this study is to identify the effects of miRNAs in the pathogenesis of DR via activating neovascularization pathways. K E Y W O R D S diabetic retinopathy (DR), microRNAs (miRNAs), neovascularization 2 | PATHOPHYSIOLOGY OF DR Hyperglycemia has been differently incorporated in the pathogenesis of retinal microvascular damage through inducing oxidative stress, polyol and hexosamine pathway activation, advanced glycation end products (AGE) formation, and the activation of protein kinase C isoforms. 3 The earliest responses of the retinal blood vessels to hyperglycemia are vasodilatation and blood flow changes. Subsequently, these J Cell Biochem. 2019;120:9514-9521. wileyonlinelibrary.com/journal/jcb 9514 |

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Microphthalmia-associated Transcription Factor (MITF) Promotes Differentiation of Human Retinal Pigment Epithelium (RPE) by Regulating microRNAs-204/211 Expression

Cited by 89 publications

References 56 publications

MicroRNAs of the RPE are essential for RPE differentiation and photoreceptor maturation

MicroRNAs of the RPE are essential for RPE differentiation and photoreceptor maturation

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

The effects of microRNAs in activating neovascularization pathways in diabetic retinopathy

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