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

Ohana, Reut; Weiman-Kelman, B.; Raviv, S.; Tamm, Ernst R.; Pasmanik‐Chor, Metsada; Rinon, Ariel; Netanely, Dvir; Shamir, Ron; Solomon, Albert; Ashery‐Padan, Ruth

doi:10.1242/dev.121533

Cited by 46 publications

(34 citation statements)

References 101 publications

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“…This result, combined with a lack of RPE morphological changes upon loss of any of the four mammalian Argonaute (AGO) family proteins involved in RNA silencing processes or of the RISC-loading complex subunit TARBP, indicated that RPE dysfunction in the absence of DICER1 is miRNA-independent. Hence, the results of our more systematic assessment of DGCR8 loss over a longer time course contrast with those findings reported previously (30). The impact of miRNA loss on mature RPE could be masked by more rapid cell death resulting from toxic SINE transcript accumulation in the absence of DICER1 (52).…”

Section: Mirnas In Mature Rpecontrasting

confidence: 97%

“…However, inhibition of both miRNAs causes a more general loss of RPE-specific gene expression accompanied by morphological changes and increased expression of genes causing epithelial to mesenchymal transition (28). RPE cell-specific miRNA loss-of-function models in animals have clearly demonstrated that miRNAs are essential for proper specification and differentiation of RPE cells (24,28,30). However, available data addressing their roles in the physiology and function of mature RPE cells in vivo are limited.…”

Section: Dicer1mentioning

confidence: 99%

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MicroRNA-processing Enzymes Are Essential for Survival and Function of Mature Retinal Pigmented Epithelial Cells in Mice

Sundermeier¹,

Sakami²,

Sahu

et al. 2017

Journal of Biological Chemistry

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Edited by Paul E. FraserAge-related macular degeneration (AMD) is a major cause of irreversible vision loss. The neovascular or "wet" form of AMD can be treated to varying degrees with anti-angiogenic drugs, but geographic atrophy (GA) is an advanced stage of the more prevalent "dry" form of AMD for which there is no effective treatment. Development of GA has been linked to loss of the microRNA (miRNA)-processing enzyme DICER1 in the mature retinal pigmented epithelium (RPE). This loss results in the accumulation of toxic transcripts of Alu transposable elements, which activate the NLRP3 inflammasome and additional downstream pathways that compromise the integrity and function of the RPE. However, it remains unclear whether the loss of miRNA processing and subsequent gene regulation in the RPE due to DICER1 deficiency also contributes to RPE cell death. To clarify the role of miRNAs in RPE cells, we used two different mature RPE cell-specific Cre recombinase drivers to inactivate either Dicer1 or DiGeorge syndrome critical region 8 (Dgcr8), thus removing RPE miRNA regulatory activity in mice by disrupting two independent and essential steps of miRNA biogenesis. In contrast with prior studies, we found that the loss of each factor independently led to strikingly similar defects in the survival and function of the RPE and retina. These results suggest that the loss of miRNAs also contributes to RPE cell death and loss of visual function and could affect the pathology of dry AMD. Age-related macular degeneration (AMD)3 is a progressive retinal degenerative disorder that preferentially impacts the macula, the central region of the retina primarily responsible for both color vision and visual acuity. AMD is the leading cause of irreversible vision loss in modern Western societies among adults over 50 and is projected to impact the lives of nearly 200 million people worldwide by the year 2020 (1-4). It presents in two distinct forms, based on the types of lesions that occur in the late stages. The neovascular or "wet" form of AMD is associated with abnormal growth of blood vessels in the choriocapillaris, which extend through Bruch's membrane and cause acute vision loss that can be reversed relatively rapidly through intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors (5-8). In contrast, the dry form of AMD is characterized by a large number of drusen and occasionally by geographic atrophy (GA), the regional loss of macular photoreceptors, retinal pigmented epithelium (RPE), and choriocapillaris. These changes cause deficits in dark adaptation, along with dense visual field scotomas and a gradual decline in visual acuity (9 -11). Currently, there is no effective treatment for the dry form of AMD.Discovered over 2 decades ago in Caenorhabditis elegans, miRNAs regulate gene expression at the post-transcriptional level (12, 13). miRNA biogenesis involves two sequential cleavage steps. The first is accomplished in the nucleus by the microprocessor complex and involves a member of the ribonucleas...

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Section: Mirnas In Mature Rpecontrasting

confidence: 97%

Section: Dicer1mentioning

confidence: 99%

MicroRNA-processing Enzymes Are Essential for Survival and Function of Mature Retinal Pigmented Epithelial Cells in Mice

Sundermeier¹,

Sakami²,

Sahu

et al. 2017

Journal of Biological Chemistry

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“…The term ‘pigmentosa’ deals with the characteristic appearance, during the advanced states of the disease, of abnormal areas of pigment in the retina. Much evidence supports the role of miRNAs in normal retinal development and functions . Alterations of miRNA regulation in conditional Dicer mouse mutant eyes reduce and damage normal development of lens, cornea, retina and optic chiasm .…”

mentioning

confidence: 98%

miRNAexpression profile of retinal pigment epithelial cells under oxidative stress conditions

et al. 2018

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Deep analysis of regulative mechanisms of transcription and translation in eukaryotes could improve knowledge of many genetic pathologies such as retinitis pigmentosa ( RP ). New layers of complexity have recently emerged with the discovery that ‘junk’ DNA is transcribed and, among these, miRNAs have assumed a preponderant role. We compared changes in the expression of mi RNA s obtained from whole transcriptome analyses, between two groups of retinal pigment epithelium ( RPE ) cells, one untreated and the other exposed to the oxidant agent oxidized low‐density lipoprotein (ox LDL ), examining four time points (1, 2, 4 and 6 h). We found that 23 mi RNA s exhibited altered expression in the treated samples, targeting genes involved in several biochemical pathways, many of them associated to RP for the first time, such as those mediated by insulin receptor signaling and son of sevenless. Moreover, five RP causative genes ( KLHL7 , RDH11 , CERKL , AIPL1 and USH1G ) emerged as already validated targets of five altered mi RNA s (hsa‐miR‐1307, hsa‐miR‐3064, hsa‐miR‐4709, hsa‐miR‐3615 and hsa‐miR‐637), suggesting a tight connection between induced oxidative stress and RP development and progression. This mi RNA expression analysis of oxidative stress‐induced RPE cells has discovered new regulative functions of mi RNA s in RP that should lead to the discovery of new ways to regulate the etiopathogenesis of RP .

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“…It has been demonstrated that miR‐155 functions to promote EAU using a global knock‐out mouse . Because microRNAs have an important role in the retina and specifically the RPE , we asked if tissue‐specific expression of miR‐155 is necessary for EAU. A doxycycline inducible RPE‐specific Cre (RPE/rtTA) expressing mouse that has been extensively characterized in multiple models was crossed with a floxed miR‐155 (miR‐155 fl/fl ) mouse to create an inducible RPE‐specific miR‐155 knock‐out.…”

Section: Resultsmentioning

confidence: 99%

Tissue‐specific production of MicroRNA‐155 inhibits melanocortin 5 receptor‐dependent suppressor macrophages to promote experimental autoimmune uveitis

et al. 2019

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Tissue-specific immune regulation is an important component of the immune response relevant to many areas of immunology. The focus of this study is on tissue-specific mechanisms that contribute to autoimmune uveitis. Precise gene regulation is necessary for the proper expression of an inflammatory or regulatory response. This precision gene regulation can be accomplished by microRNA at the level of the mRNA transcript. miR-155, in particular, has a complicated role in the immune response with positive and negative inflammatory effects. In this work, we identify a decrease in miR-155 in suppressor macrophages and further examine how tissue-specific production of miR-155 impacts experimental autoimmune uveitis. Importantly, we show that eliminating miR-155 expression by the target tissue before initiation reduces disease severity, but elimination of miR-155 after the onset of inflammation does not alter the course of disease. Additionally, expression of miR-155 by the target tissue before initiation is necessary for the induction of regulatory immunity that protects from further autoimmune disease, but not after the onset of inflammation. In summary, we find a MC5r-dependent decrease in miR-155 in postexperimental autoimmune uveitis APC, miR-155 production by the target tissue is necessary for the initiation of autoimmune uveitis, and may have a role in establishing protective regulatory immunity.Keywords: Autoimmunity r Experimental autoimmune uveitis r Macrophages r miR-155Additional supporting information may be found online in the Supporting Information section at the end of the article.

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

Cited by 46 publications

References 101 publications

MicroRNA-processing Enzymes Are Essential for Survival and Function of Mature Retinal Pigmented Epithelial Cells in Mice

MicroRNA-processing Enzymes Are Essential for Survival and Function of Mature Retinal Pigmented Epithelial Cells in Mice

miRNAexpression profile of retinal pigment epithelial cells under oxidative stress conditions

Tissue‐specific production of MicroRNA‐155 inhibits melanocortin 5 receptor‐dependent suppressor macrophages to promote experimental autoimmune uveitis

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