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J. Biol. Chem., Vol. 277, Issue 19, 17016-17022, May 10, 2002
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From the 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. We found that Mertk protein is absent from RCS, but not wild-type, tissues and cultured RPE
cells. Delivery of rat Mertk to cultured RCS RPE cells by means of a recombinant adenovirus restored the cells to complete phagocytic competency. Infected RCS RPE cells ingested exogenous outer
segments to the same extent as wild-type RPE cells, but outer segment
binding was unaffected. Mertk protein progressively co-localized with
outer segment material during phagocytosis by primary RPE cells, and
activated Mertk accumulated during the early stages of phagocytosis by
RPE-J cells. We conclude that Mertk likely functions directly in the
RPE phagocytic process as a signaling molecule triggering outer segment ingestion.
Mertk Triggers Uptake of Photoreceptor Outer Segments during
Phagocytosis by Cultured Retinal Pigment Epithelial Cells*
,
Department of Genetics, Stanford University
School of Medicine, Stanford, California 94305-5120 and the
§ Departments of Anatomy and Ophthalmology, University of
California, San Francisco School of Medicine, San
Francisco, California 94143-0730
*
This work was supported by a postdoctoral fellowship from
the Fight for Sight research division of Prevent Blindness America (to
W. F.), by grants from the Ruth and Milton Steinbach Fund and the Karl
Kirchgessner Foundation (to D. V.), by National Institutes of Health
Grants EY01919, EY02162, and EY06842, the Foundation Fighting
Blindness, and the Macula Vision Research Foundation (to M. M. L.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.:
650-723-3290; Fax: 650-723-7016; E-mail:
vollrath@genome.stanford.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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