Rod and cone specific domains in the interphotoreceptor matrix

Mieziewska, Kristina; Veen, Theo van; Murray, John M.; Aguirre, Gustavo D.

doi:10.1002/cne.903080305

Cited by 32 publications

(23 citation statements)

References 20 publications

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“…6O-Q). In the controls, PNA labeled the insoluble extracellular matrix domain that enveloped the RPE cone apical sheath, and cone OS and IS (29). In the 6-week-old affected dog, PNA labeling was observed around the distorted cone IS, and locations (Inset): two inferior loci (left), two superior loci (middle), and a central locus are shown (right).…”

Section: Incomplete Development Of Cones But Normal Cone Insoluble Ementioning

confidence: 99%

“…This complex, insoluble structure of poorly understood origin (29), forms an 'exoskeleton' that surrounds the RPE cone sheath, and cone IS and OS, and in photoreceptor degenerations it adjusts to the contours of the diseased cells (38). Preservation of this matrix domain will be critical for future studies with corrective gene therapy in order to provide the appropriate extracellular environment that would allow treated cones to regrow their OS.…”

Section: Developmental Abnormalities Of the Outer Retina And Oplmentioning

confidence: 99%

“…Mitotic cells were visualized by Phospho-histone H3 (PHH3) labeling (50,51), and apoptotic nuclei by TUNEL (terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling) labeling performed according to the manufacturer's instructions (Roche, Indianapolis, IN). Peanut agglutinin (PNA) labeling was used to label the cone insoluble extracellular matrix domain (29), and done by incubating tissue sections in fluorescently-tagged PNA for 1 hour. Cell nuclei were stained with DAPI (49,69-diamino-2-phenylindole).…”

Section: Anatomic and Immunohistochemical Studiesmentioning

confidence: 99%

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Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused byNPHP5mutation

et al. 2016

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Ciliary defects can result in severe disorders called ciliopathies. Mutations in NPHP5 cause a ciliopathy characterized by severe childhood onset retinal blindness, Leber congenital amaurosis (LCA), and renal disease. Using the canine NPHP5-LCA model we compared human and canine retinal phenotypes, and examined the early stages of photoreceptor development and degeneration, the kinetics of photoreceptor loss, the progression of degeneration and the expression profiles of selected genes. NPHP5-mutant dogs recapitulate the human phenotype of very early loss of rods, and relative retention of the central retinal cone photoreceptors that lack function. In mutant dogs, rod and cone photoreceptors have a sensory cilium, but develop and function abnormally and then rapidly degenerate; L/M cones are more severely affected than S-cones. The lack of outer segments in mutant cones indicates a ciliary dysfunction. Genes expressed in mutant rod or both rod and cone photoreceptors show significant downregulation, while those expressed only in cones are unchanged. Many genes in celldeath and -survival pathways also are downregulated. The canine disease is a non-syndromic LCA-ciliopathy, with normal renal structures and no CNS abnormalities. Our results identify the critical time points in the pathogenesis of the photoreceptor disease, and bring us closer to defining a potential time window for testing novel therapies for translation to patients. †

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Section: Incomplete Development Of Cones But Normal Cone Insoluble Ementioning

confidence: 99%

Section: Developmental Abnormalities Of the Outer Retina And Oplmentioning

confidence: 99%

Section: Anatomic and Immunohistochemical Studiesmentioning

confidence: 99%

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Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused byNPHP5mutation

et al. 2016

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“…The lectin blots were visualized by UV light and photographed by a Photocapt MW documentation system (IP-215-SD version 99.03, equipped with UV/white light lamps, CCD camera XC-75CE, video and video laser printer, Sony Corp., Tokyo, Japan). WGA reacts with (N-acetyl ␤ -D-glucosamine) 2 /sialic acid and PNA does so with D-galactose-␤ 1 ] 3 N-acetyl galactosamine [30] . The terminal sugars sialic acid and D-galactose of these disaccharide units of proteoglycans/sGAG are recognized by WGA and PNA, respectively.…”

Section: Characterization Of Sgag/proteoglycanmentioning

confidence: 99%

<i>rd1 </i>Mouse Retina Shows Imbalance in Cellular Distribution and Levels of TIMP-1/MMP-9, TIMP-2/MMP-2 and Sulfated Glycosaminoglycans

Ahuja

Caffé

et al. 2006

Ophthalmic Res

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Background: The rd1 mouse retina displays fast degeneration of photoreceptors resulting in a depletion of almost all rod photoreceptors by postnatal day 21 (PN21). To evaluate the role of proteinases in the pathophysiology of this animal model of retinitis pigmentosa, C3H rd1 and congenic wild-type (wt) mice retinas were analyzed. Material and Methods: The cellular localization and levels of proteins, matrix metalloproteinases (MMPs), their endogenous inhibitors (TIMPs), total sulfated glycosaminoglycans (sGAG) and nature of saccharides in rd1 and wt retinal extracts were compared. Results: MMP-2/TIMP-2 and MMP-9/TIMP-1 were predominantly localized in the interphotoreceptor matrix (IPM) of both genotypes, but MMP-2/TIMP-2 also appeared in the Müller cell fibers of rd1 retina. In rd1 retinal extracts the levels of total proteins were lower and those of active MMP-9, MMP-2, TIMP-1 and total sGAG were higher than those of wt extracts. Despite an increase in TIMP-1, active MMP-9/MMP-2 were disproportionately elevated in rd1 compared to wt retina. With increasing age, MMPs in wt retinas were decreased but were increased in rd1. The sialylation of proteoglycans in PN2 and PN7 rd1 retinas was lower, and galactosylation was higher than that in wt retinas. Conclusions: MMP-9/MMP-2 and TIMP-1/TIMP-2 are associated with IPM, possibly after secretion by retinal pigmented epithelial cells. In degenerating rd1 retina, MMP-2/TIMP-2 are associated with the Müller cell fibers, which apparently play a central role in modifying the balance between MMPs and TIMPs. Elevated sGAG and proteolysis due to an imbalance in the levels of TIMPs and active MMP-9/MMP-2 in rd1 retina possibly contribute to retinal degeneration in the rd1 mouse.

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“…6, white arrows). To study this further, we performed double-immunofluorescence labeling using ENO2 in combination with lectin PNA and lectin WGA, which label cone photoreceptor inner segments and rod photoreceptor outer segments, respectively 29 (Figs. 7, 8).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Laser Capture Microdissection-Directed Profiling of Glycolytic and mTOR Pathways in Areas of Selectively Ablated Müller Cells in the Murine Retina

Chung¹,

Shen²,

Gillies³

2013

Invest. Ophthalmol. Vis. Sci.

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Citation: Chung SH, Shen W, Gillies MC. Laser capture microdissectiondirected profiling of glycolytic and mTOR pathways in areas of selectively ablated müller cells in the murine retina. Invest Ophthalmol Vis Sci. 2013;54:6578-6584. DOI:10.1167/ iovs.13-12311 PURPOSE. We have reported previously down-regulation of key metabolic pathways, the glycolytic and mTOR pathways, from a global retinal microarray analysis after selective Müller cell ablation in a novel transgenic model. The purpose of the present study was to examine changes in expression of key molecules of glycolytic and mTOR pathways specifically in patches of Müller cell loss.METHODS. Eyes were enucleated 1 and 3 months after induced Müller cell ablation, directly embedded in optimal cutting temperature medium, and snap frozen in liquid nitrogen. Laser capture microdissection (LCM) was conducted to dissect patches of Müller cell loss for quantitative RT-PCR (qRT-PCR) analysis of key genes of the glycolytic (glyceraldehyde-3-phosphate dehydrogenase, enolase 1 and 2, lactate dehydrogenase A and B) and mTOR pathways (insulin-like growth factor receptor 1, phosphatidylinositide-3-kinase, Akt1, and regulatory-associated protein of mTOR). Protein validations were performed by immunohistochemistry. RESULTS. The LCM-directed qRT-PCR analysis ofMüller cell ablated specimens demonstrated reduced transcription of genes involved in the glycolytic and mTOR metabolic pathways. Of the proteins we chose to study, only enolase 1 was expressed by Müller cells. Other glycolytic and mTOR pathway proteins were expressed by photoreceptor inner and outer segments, which were lost in patches of Müller cell ablation.CONCLUSIONS. We found suppression of genes encoding various glycolytic and mTOR pathwayassociated enzymes in areas of Müller cell loss. This appeared mainly to be due to loss of photoreceptor inner and outer segments. The consequences of metabolic derangement caused by Müller cell ablation warrant further investigation.Keywords: Müller cells, glycolysis, mTOR pathway, photoreceptors, laser capture microdissection M¨u ller cells are the principal glial cells of the mammalian retina. They provide an anatomic and functional link between retinal neurons and their surrounding compartments, since they span the entire thickness of the retina from the microvilli projecting from the outer limiting membrane, formed by the apical processes of Müller cells, to the Müller cell end feet, which form the inner limiting membrane. They have critical roles in maintaining retinal homeostasis, such as producing neuroactive substances through a neurotransmitter recycling system, 1 maintaining the blood-retinal barrier (BRB), 2 and regulating ion, water content, and pH. 3,4 Müller cells also provide metabolic support and nutrients to neurones via metabolic pathways, such as the glycolytic pathway. 5 There is strong evidence that the Müller cell is one of the major cells responsible for metabolizing glucose into pyruvate and lactate to fuel neurons in the retina. [6][7][8][9][10][11...

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Rod and cone specific domains in the interphotoreceptor matrix

Cited by 32 publications

References 20 publications

Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused byNPHP5mutation

Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused byNPHP5mutation

<i>rd1 </i>Mouse Retina Shows Imbalance in Cellular Distribution and Levels of TIMP-1/MMP-9, TIMP-2/MMP-2 and Sulfated Glycosaminoglycans

Laser Capture Microdissection-Directed Profiling of Glycolytic and mTOR Pathways in Areas of Selectively Ablated Müller Cells in the Murine Retina

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