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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.

          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

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              Characterization of a novel member of the macrophage mannose receptor type C lectin family.

              The recognition of a diversity of carbohydrates by the various calcium dependent (type C) lectin family members has been shown to be critical for a variety of processes ranging from cell adhesion to antigen presentation. Examination of the expressed sequence tag (EST) data base for novel type C lectins using E-selectin as a probe resulted in the identification of a distantly related short polypeptide sequence containing many of the conserved residues found in these carbohydrate-binding proteins. Cloning of the full-length murine cDNA containing this region revealed that this protein is a novel member of the family that includes the macrophage mannose, the phospholipase A2, and the DEC 205 receptors, with a cysteine-rich domain, a fibronectin type 2 domain, eight type C lectin domains, a transmembrane domain, and a short cytoplasmic carboxyl terminus. Genomic Southern analysis suggests that this is a conserved protein, and examination of a human homologue revealed a high degree of sequence homology with the murine form. Northern blot analysis revealed expression of a large transcript in a number of different human and murine tissues and tumor cells and an alternatively spliced smaller transcript with a divergent 5' sequence was expressed specifically in the human fetal liver. Analysis of the genomic structure revealed that the gene encoding this lectin was interrupted by a large number of introns, and the intron structure was similar to the macrophage mannose receptor gene. Finally, in situ hybridization analysis demonstrated that the transcript encoding this lectin was found in a number of highly endothelialized sites as well as in chondrocytes in cartilaginous regions of the embryo.
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                Author and article information

                Journal
                ORE
                Ophthalmic Res
                10.1159/issn.0030-3747
                Ophthalmic Research
                S. Karger AG
                0030-3747
                1423-0259
                2003
                February 2003
                30 January 2003
                : 35
                : 1
                : 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
                68198 Ophthalmic Res 2003;35:42–47
                10.1159/000068198
                12566862
                © 2003 S. Karger AG, Basel

                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.

                Page count
                Figures: 1, Tables: 2, References: 33, Pages: 6
                Categories
                Original Paper

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