The Royal College of Surgeons Rat: An Animal Model for Inherited Retinal Degeneration with a Still Unknown Genetic Defect

Strauß, Olaf; Stumpff, Friederike; Mergler, Stefan; Wienrich, M.; Wiederholt, Michael

doi:10.1159/000046474

Cited by 89 publications

(59 citation statements)

References 67 publications

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“…Moreover, the fact that Ad-Mertk-infected RCS cells bound and ingested OS at wild-type levels demonstrates that the rest of the phagocytic machinery in RCS RPE is normal and that RCS RPE cells have the same potential as wild-type RPE for OS internalization. Reported biochemical abnormalities of RCS RPE, such as increased calcium membrane conductance and altered cAMP and inositol phosphate second messenger metabolism (31) OS binding receptor for RPE in cell culture (12,14). However, ␣ v ␤ 5 integrin cannot be essential for retinal structure and function because mice with a targeted disruption of the ␤ 5 gene have normal retinal anatomy and electroretinography at 1 and 4 months of age, 2 despite the fact that disc shedding and phagocytosis begin around P12.…”

Section: Discussionmentioning

confidence: 99%

Mertk Triggers Uptake of Photoreceptor Outer Segments during Phagocytosis by Cultured Retinal Pigment Epithelial Cells

Feng¹,

Yasumura²,

Matthes³

et al. 2002

Journal of Biological Chemistry

208

141

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The RCS rat is a widely studied model of recessively inherited retinal degeneration. The genetic defect, known as rdy (retinal dystrophy), results in failure of the retinal pigment epithelium (RPE) to phagocytize shed photoreceptor outer segment membranes. We previously used positional cloning and in vivo genetic complementation to demonstrate that Mertk is the gene for rdy. We have now used a rat primary RPE cell culture system to demonstrate that the RPE is the site of action of Mertk and to obtain functional evidence for a key role of Mertk in RPE phagocytosis. Phagocytosis is a process by which large particles are internalized by cells to form phagosomes. The process can be divided into three phases: binding, ingestion, and digestion. Retinal pigment epithelial (RPE) 1 cells, which form a polarized epithelium between the photoreceptor cells and the choroid in the outer retina, phagocytize more biomass than any other mammalian cell type (1). The RPE phagocytizes photoreceptor outer segment (OS) membranes (2) that are shed as part of the normal ongoing process of photoreceptor OS renewal (3). Failure of OS membrane uptake leads to photoreceptor cell death (4), as illustrated by the RCS rat, a widely used model for recessively inherited retinal degeneration. The RCS mutation rdy (retinal dystrophy) causes, either directly or indirectly, a defect in RPE phagocytosis (4). This defect leads to an accumulation of shed OS membranes in the subretinal space (4) and a rapid and progressive degeneration of photoreceptor cells (5).The molecular mechanisms of RPE phagocytosis are unclear. Studies of the internalization of exogenous OS by cultured primary RPE cells suggested a receptor-mediated process (6 -8). Inhibition of the RPE cell culture phagocytic assay by antireceptor antibodies or competitive ligands suggested several specific proteins that might play a role in the process, including the mannose receptor (9, 10), CD36 (11), and ␣ v ␤ 5 integrin (12-14). Inhibition of ␣ v ␤ 5 integrin function disrupts the OS binding phase of RPE phagocytosis, whereas the mannose receptor and CD36 have been implicated in both OS binding and ingestion. Cultured RCS RPE cells bind exogenous OS at wildtype levels. However, only a small percentage of bound OS are ingested by RCS RPE cells (15), indicating that the protein encoded by the rdy locus is critical, directly or indirectly, for OS uptake.The gene corresponding to rdy remained unknown until recently. The mannose receptor protein and messenger RNA are present in the RPE of both wild-type and RCS rats from postnatal day (P) 5 to adult (16). CD36 null mice have been reported to have normal electroretinography and retinal histology (17). These data suggest that neither the mannose receptor nor CD36 is the gene mutated in the RCS rat. We used positional cloning to identify a mutation in the receptor tyrosine kinase gene Mertk in the RCS rat. A deletion of RCS genomic DNA results in expression of an aberrant Mertk transcript with a translation termination signal after codon 20 (18),...

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Section: Discussionmentioning

confidence: 99%

Mertk Triggers Uptake of Photoreceptor Outer Segments during Phagocytosis by Cultured Retinal Pigment Epithelial Cells

Feng¹,

Yasumura²,

Matthes³

et al. 2002

Journal of Biological Chemistry

208

141

View full text Add to dashboard Cite

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“…Normal adult Sprague-Dawley (SD) rats (180-200 g), Balb/c mice (18-20 g), and Royal College of Surgeons (RCS) rats (3 weeks old), an animal model for inherited retinal degeneration, 32 were obtained from Shanghai Laboratory Animal Center (SLAC). All animals were treated, maintained, and sacrificed in accordance with the policies specified in the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and the guidelines approved by national and local institutions.…”

Section: Subretinal Injectionmentioning

confidence: 99%

Enhancement of rAAV2-Mediated Transgene Expression in Retina Cells In Vitro and In Vivo by Coadministration of Low-Dose Chemotherapeutic Drugs

Zhang

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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“…Basal membrane of the RPE is in contact with Bruch membrane, whereas the apical membrane faces the photoreceptor outer segments. The close structural interactions of RPE cells with the outer retina indicate that the major functions of the RPE layer are to maintain the survival and normal functioning of photoreceptors by controlling nutrients/waste products exchange (2), phagocytosing shed outer segments (3), shuttling retinoids to synthesize visual pigments (4), and producing trophic factors necessary for photoreceptor survival. Failure of any one of these functions can result in degeneration of the retina, loss of visual function, and blindness.…”

Section: The Retinal Pigment Epithelium (Rpe)mentioning

confidence: 99%

α2 but Not α1 AMP-activated Protein Kinase Mediates Oxidative Stress-induced Inhibition of Retinal Pigment Epithelium Cell Phagocytosis of Photoreceptor Outer Segments

Qin

Vries

2008

Journal of Biological Chemistry

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Oxidative stress causes retinal pigment epithelium (RPE) cell dysfunction and is a major risk factor leading to the development of dry-type age-related macular degeneration. Taking pharmacological and genetic approaches, we address the mechanisms by which sublethal oxidative stress inhibits RPE cell phagocytosis. Sublethal oxidative stress dose-dependently inhibited RPE cell phagocytosis of photoreceptor outer segments (POS) and activated AMP-activated protein kinase (AMPK) as determined by increased Thr 172 and Ser 79 phosphorylation of AMPK␣ and its substrate acetyl-CoA carboxylase, respectively. Similar to oxidative stress, 5-aminoimidazole-4-carboxamide riboside (AICAR), a pharmacological activator of AMPK, inhibited RPE cell phagocytosis of POS in a dose-dependent manner. Inhibition of RPE cell phagocytosis by AICAR was fully reversed by blockade of AICAR translocation into cells by dipyridamole or inhibition of AICAR conversion to ZMP by adenosine kinase inhibitor 5-iodotubercidin. In agreement, AICAR-induced activation of AMPK was abolished by preincubation with dipyridamole or 5-iodotubercidin. Knock-out experiments further revealed that ␣2 but not ␣1 AMPK was involved in RPE cell phagocytosis and that activation of ␣2 AMPK contributed to the inhibition of RPE cell phagocytosis by oxidative stress. Inhibition of RPE cell phagocytosis by activation of ␣2 AMPK was associated with a dramatic increase in acetyl-CoA carboxylase phosphorylation. In comparison, AMPK had no role in oxidative stress-induced breakdown of RPE barrier function. Taken together, reduction in POS load under oxidative stress might direct RPE cells to a self-protected status. Thus, activating AMPK could have therapeutic potential in treating dry macular degeneration.The retinal pigment epithelium (RPE) 2 is a monolayer of pigmented cells forming a part of the blood-retina barrier (1). Basal membrane of the RPE is in contact with Bruch membrane, whereas the apical membrane faces the photoreceptor outer segments. The close structural interactions of RPE cells with the outer retina indicate that the major functions of the RPE layer are to maintain the survival and normal functioning of photoreceptors by controlling nutrients/waste products exchange (2), phagocytosing shed outer segments (3), shuttling retinoids to synthesize visual pigments (4), and producing trophic factors necessary for photoreceptor survival. Failure of any one of these functions can result in degeneration of the retina, loss of visual function, and blindness.Age-related macular degeneration (AMD) is an idiopathic retinal degenerative disease that predominates in the elderly in the Western world as a cause of irreversible, profound vision loss (5, 6). The pathogenic mechanisms whereby environmental factors contribute to the development of AMD remain elusive. However, growing evidence indicates that oxidative stress injury to the RPE plays an important role in the etiology of AMD. The RPE is at high risk for oxidative injury due to its location in a highly oxygenated envi...

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The Royal College of Surgeons Rat: An Animal Model for Inherited Retinal Degeneration with a Still Unknown Genetic Defect

Cited by 89 publications

References 67 publications

Mertk Triggers Uptake of Photoreceptor Outer Segments during Phagocytosis by Cultured Retinal Pigment Epithelial Cells

Mertk Triggers Uptake of Photoreceptor Outer Segments during Phagocytosis by Cultured Retinal Pigment Epithelial Cells

Enhancement of rAAV2-Mediated Transgene Expression in Retina Cells In Vitro and In Vivo by Coadministration of Low-Dose Chemotherapeutic Drugs

α2 but Not α1 AMP-activated Protein Kinase Mediates Oxidative Stress-induced Inhibition of Retinal Pigment Epithelium Cell Phagocytosis of Photoreceptor Outer Segments

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