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      Transcription of a Single Mannose Receptor Gene by Macrophage and Retinal Pigment Epithelium

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          Abstract

          To determine if the macrophage mannose receptor transcript is present in mouse, rat, pig, and human retinal pigment epithelium (RPE), primary cultures and/or freshly dissected retinal pigment epithelium from four different species were used to isolate total RNA. RT-PCR was used to amplify segments of the macrophage mannose receptor from each sample. Amplified products were sequenced and compared with known sequences of the macrophage mannose receptor. Macrophage mannose receptor transcripts were identified in all RPE samples. Comparison between sequences identified in RPE with macrophage sequences from the same species revealed 100% identity. Sequence homology between the different species was 74% or greater. These data are consistent with the transcription of a single mannose receptor gene by these two phagocytic cell types.

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          Correction of the retinal dystrophy phenotype of the RCS rat by viral gene transfer of Mertk.

          Jacque L. Duncan, Denise Kay, D Vollrath … (2001)
          The Royal College of Surgeons (RCS) rat is a widely studied animal model of retinal degeneration in which the inability of the retinal pigment epithelium (RPE) to phagocytize shed photoreceptor outer segments leads to a progressive loss of rod and cone photoreceptors. We recently used positional cloning to demonstrate that the gene Mertk likely corresponds to the retinal dystrophy (rdy) locus of the RCS rat. In the present study, we sought to determine whether gene transfer of Mertk to a RCS rat retina would result in correction of the RPE phagocytosis defect and preservation of photoreceptors. We used subretinal injection of a recombinant replication-deficient adenovirus encoding rat Mertk to deliver the gene to the eyes of young RCS rats. Electrophysiological assessment of animals 30 days after injection revealed an increased sensitivity of treated eyes to low-intensity light. Histologic and ultrastructural assessment demonstrated substantial sparing of photoreceptors, preservation of outer segment structure, and correction of the RPE phagocytosis defect in areas surrounding the injection site. Our results provide definitive evidence that mutation of Mertk underlies the RCS retinal dystrophy phenotype, and that the phenotype can be corrected by treatment of juvenile animals. To our knowledge, this is the first demonstration of complementation of both a functional cellular defect (phagocytosis) and a photoreceptor degeneration by gene transfer to the RPE. These results, together with the recent discovery of MERTK mutations in individuals with retinitis pigmentosa, emphasize the importance of the RCS rat as a model for gene therapy of diseases that arise from RPE dysfunction.
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            Phagocytosis of rod outer segments by retinal pigment epithelial cells requires  v 5 integrin for binding but not for internalization

            V. Bonilha, S. Finnemann, A. D. Marmorstein … (1997)
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              Outer segment phagocytosis by cultured retinal pigment epithelial cells requires Gas6.

              M Obin, Kim B Burgess, M Heeb … (2001)
              The function and viability of vertebrate photoreceptors requires the daily phagocytosis of photoreceptor outer segments (OS) by the adjacent retinal pigment epithelium (RPE). We demonstrate here a critical role in this process for Gas6 and by implication one of its receptor protein tyrosine kinases (RTKs), Mertk (Mer). Gas6 specifically and selectively stimulates the phagocytosis of OS by normal cultured rat RPE cells. The magnitude of the response is dose-dependent and shows an absolute requirement for calcium. By contrast the Royal College of Surgeons (RCS) rat RPE cells, in which a mutation in the gene Mertk results in the expression of a truncated, non-functional receptor, does not respond to Gas6. These data strongly suggest that activation of Mertk by its ligand, Gas6, is the specific signaling pathway responsible for initiating the ingestion of shed OS. Moreover, photoreceptor degeneration in the RCS rat retina, which lacks Mertk, and in humans with a mutation in Mertk, strongly suggests that the Gas6/Mertk signaling pathway is essential for photoreceptor viability. We believe that this is the first demonstration of a specific function for Gas6 in the eye. Copyright 2001 Academic Press.
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                Author and article information

                Journal
                Journal ID (publisher-id): ORE
                Journal ID (nlm-ta): Ophthalmic Res
                Journal ID (doi): 10.1159/issn.0030-3747
                Title: Ophthalmic Research
                Publisher: S. Karger AG
                ISSN (Print): 0030-3747
                ISSN (Electronic): 1423-0259
                Publication date Subscription-year: 2003
                Publication date (Print): February 2003
                Publication date (Electronic): 30 January 2003
                Volume: 35
                Issue: 1
                Pages: 42-47
                Affiliations
                aDepartment of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Ky., bDepartment of Medicine and Biochemistry, Vanderbilt University, and VAMC, Nashville, Tenn., USA
                Article
                Publisher ID: 68198 Other ID: Ophthalmic Res 2003;35:42–47
                DOI: 10.1159/000068198
                PubMed ID: 12566862
                SO-VID: 4064fdb9-4a6a-4725-9cc9-04a41333def1
                Copyright © © 2003 S. Karger AG, Basel
                License:

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                Date received : 23 August 2002
                Date accepted : 24 September 2002
                Page count
                Figures: 1, Tables: 2, References: 33, Pages: 6
                Categories
                Subject: Original Paper

                ScienceOpen disciplines: Vision sciences,Ophthalmology & Optometry,Pathology
                Keywords: Phagocytosis,Gene expression,Macrophage,Mannose receptor,Retinal pigment epithelium
                Data availability:
                ScienceOpen disciplines: Vision sciences, Ophthalmology & Optometry, Pathology
                Keywords: Phagocytosis, Gene expression, Macrophage, Mannose receptor, Retinal pigment epithelium

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