RCS Rats Research Articles

Integrin αvβ5 is not required for the phagocytosis of photoreceptor outer segments by cultured retinal pigment epithelial cells

The phagocytosis of photoreceptor outer segments (OS) by the retinal pigment epithelium (RPE) is a receptor mediated process. A key component of this process is the receptor tyrosine kinase, Mer. RPE cells from the RCS rat, which lacks a functional mer gene, and do not express Mer protein, are able to bind OS, but are unable to ingest them, suggesting that both a binding receptor and an ingestion receptor (Mer) are required for phagocytosis to occur. These rats become blind shortly after birth. To date the binding receptor has not been identified. Recent studies, using an SV40 transformed rat RPE cell line, RPE-J, or cultured human RPE cells, have suggested that the receptor for OS binding is the integrin αvβ5. However, the results presented here clearly show that this integrin plays at most a minor role in the phagocytosis of OS by primary cultures of rat RPE cells. OS phagocytosis by normal RPE cells is not affected by a function-blocking antibody to αvβ5 integrin, nor by the integrin-specific blocking peptide GRGDSP. Additionally, RPE-J cells do not express the Mer receptor protein, which has been shown to be obligatory for OS phagocytosis, or RPE65, a specific marker for RPE cells. We suggest that the RPE-J cell line is not a valid model with which to study the complex process of OS phagocytosis.

Retinal transplantation of neural progenitor cells derived from the brain of GFP transgenic mice

Neural progenitor cells isolated from the brains of neonatal GFP transgenic mice were grafted to the retina of RCS rats and rds and B6 mice. Expression of GFP and differentiation markers was evaluated at 1–4 weeks post-transplantation. Grafted cells maintained transgene expression throughout the 4-week period. At 1 week there was widespread migration of GFP + cells within the host retina and at 2 weeks evidence of neuronal differentiation (as shown by both marker expression and cell morphology), although integration at 4 weeks was limited to syngeneic recipients. Because brain-derived neural progenitor cells exhibit both neuronal and astrocytic differentiation in diseased and normal host retina, these cells provide a useful tool for studies of retinal regeneration.

Practical considerations of recombinant adeno‐associated virus‐mediated gene transfer for treatment of retinal degenerations

Photoreceptor (PR) and retinal pigment epithelium (RPE) are the principal cell targets in retinal gene therapy. Recombinant adeno-associated virus (rAAV) has emerged as a very promising vector for gene therapy in hereditary retinal diseases. Gene transfer at different stages of the disease is a practical consideration for future clinical application. A rAAV carrying the enhanced green fluorescent protein gene driven by a cytomegalovirus promoter was produced by either co-infecting the 293 cell line with E1-defective adenovirus and purified by CsCl(2) density gradient (CsCl(2)-rAAV), or by transfecting with an adenoviral helper plasmid and purified by iodixanol density gradient followed by heparin column chromatography (heparin-rAAV). The impact of different virus preparations on the patterns of transgene expression was investigated after subretinal injection. Furthermore, rAAV-mediated gene transfer was evaluated at both early and advanced stages of retinal degeneration in four disease models including the RCS rat, rd, RPE(65) (-)/(-) and cathepsin D mutant mice that are associated with PR- or RPE-related gene defects. CsCl(2)-rAAV predominantly transduced RPE and with less efficiency in PR. In contrast, heparin-rAAV predominantly transduced PR but with much less efficiency in RPE. Subretinal injection of either rAAV preparation induced no changes to retinal morphology and retinal-choroidal vasculature. The product of transgene, however, could be observed in multiple tracts in the brain. In the four disease models, target cells were efficiently transduced not only at the early stage, but also at the late stage of disease as long as the target cells were present. Different preparations of rAAV have an impact on the patterns of transgene expression after subretinal injection. Patients at advanced stages of retinal degeneration may still benefit from rAAV-mediated gene therapy. The possible side effects of transgenic products on the central nervous system should be carefully monitored once therapeutic genes are employed.

An RCS-like retinal dystrophy phenotype in mer knockout mice.

To determine whether mice that are homozygous for a targeted disruption of the Mer receptor tyrosine kinase gene (mer(kd)) manifest a retinal dystrophy phenotype similar to RCS rats, which carry a mutation in the orthologous gene MERTK: Eyes of mer(kd) and C57BL/6 wild-type (WT) mice were examined by light and electron microscopy, whole-eye rhodopsin measurement, and Ganzfeld electroretinography (ERG). The mer(kd) mice showed rapid, progressive degeneration of the photoreceptors (PRs). Features of the phenotype common to mer(kd) mice and RCS rats included the absence or near absence of phagosomes in the retinal pigment epithelium (RPE) at the peak of outer segment (OS) disc shedding, accumulation of debris and whorls of membranes at the RPE-OS interface, transient supernormal rhodopsin content and OS lengths, the presence of OS vacuoles beginning at early ages, and a relatively slow removal of pyknotic PR nuclei. Most PRs were missing, and OS debris was removed by approximately postnatal day (P)45. Scotopic ERG responses were lower than age-matched WT responses and declined with PR loss. Photopic responses were preserved better than scotopic responses, corresponding with preferential cone preservation as judged histologically. ERG amplitudes were usually unmeasurable beyond P40, although a small-amplitude scotopic threshold response (STR) could still be elicited at P253 in some mice when only scattered PR nuclei remained. Ablation of Mer function in mer(kd) mice results in a retinal phenotype almost identical with that of RCS rats. The similarity in phenotypes between the two rodent models suggests that an RPE phagocytic defect is a feature of all types of retinal degeneration caused by loss of function of Mer tyrosine kinase, perhaps including mutations in human MERTK.

Inherited retinal dystrophy in Mer knockout mice.

Abnormalities of the retinal pigment epithelial (RPE) cells are seen in several inherited degenerations such as Best disease (Petrukhin et al., 1998; Marmorstein et al., 2000), Stargardt disease (Weng et al., 1999), Sorsby’s fundus dystrophy (Steinmetz et al., 1992; Jacobson et al., 1995), and childhood-onset severe retinal dystrophy (Gu et al., 1997) and Leber congenital amaurosis due to RPE65 mutations (Marlhens et al., 1997; Morimura et al., 1998; Lotery et al., 2000; Thompson et al., 2000). RCS rats have been studied extensively as a model of photoreceptor (PR)-RPE cell interactions (Mullen and LaVail, 1976; LaVail, 2001) and retinal degeneration (Strauss et al., 1998; LaVail, 2001). Retinal degeneration in RCS results from failure of the RPE to phagocytize shed rod outer segments (OS) (Herron et al., 1969; Bok and Hall, 1971). The unphagocytized OS membranes form membranous whorls at the RPE surface, and the rod OS grow abnormally long (Dowling and Sidman, 1962; LaVail and Battelle, 1975). Eventually, the OS layer degenerates into a debris zone with subsequent PR cell death (Dowling and Sidman, 1962).KeywordsRetinal DegenerationRetinal DystrophyStargardt DiseaseVitelliform Macular DystrophyScotopic Threshold ResponseThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Limitation of anatomical integration between subretinal transplants and the host retina.

In previous studies of subretinal transplantation in rabbits, the host photoreceptor layer seemed to prevent the bridging of neuronal fibers between the graft and the host retina. The current study was undertaken to determine whether the same phenomenon occurs in transplants to the subretinal space of the vascularized retina of rats. Bridging of fibers was examined in transplants to animals of different genetic backgrounds (normal versus dystrophic rats), of different ages, and after different survival times. Sprague-Dawley (SD) rat retinal tissue from embryonic day (E)18 was subretinally grafted to adult (60-day-old) normal SD rats, to RCS rats (32 and 73 days old), and to adult (60-day-old) transgenic P23H rats. After various survival times (28-183 days), transplanted retinas were processed for routine histology and immunocytochemistry. Antibodies against calbindin, neuronal nitric oxide synthase (NOS), and protein kinase C (PKC) were used to identify specific retinal cell types and their processes. The shape and position of the immunoreactive cell bodies indicated that the expected neuronal populations were labeled within the grafts and in the host retina. Labeled neuronal processes were also observed. In each case, NOS-, calbindin-, and PKC-immunolabeled fibers formed bridges between the graft and the host tissues. However, regardless of the extent of host photoreceptor cell loss, the age of the recipient, or the genetic background, bridging fibers were observed only in areas where the host photoreceptor layer was discontinuous or completely missing. The present study demonstrates that the host photoreceptor layer plays a role in limiting graft-host anatomical integration.

Evaluation of inner retinal structure in the aged RCS rat.

In retinal diseases such as retinitis pigmentosa (RP), photoreceptors degenerate while inner retinal layers are relatively spared. In these cases, it is thought that, if given a signal, the “healthy” inner retina would be capable of processing visual information in a somewhat normal fashion. Several laboratories are testing treatments designed to replace lost photoreceptors by transplanting healthy retinal tissue (Woch et al., 2001; Coffey et al., 2002) or implanting a light sensitive prosthetic device (Chow et al., 2001; Zrenner et al., 1999) into the subretinal space. These strategies will work only if the inner retina is intact and functional. Recent evidence in humans as well as rodent models of RP shows that, especially at later stages of disease progression, the inner retina begins to exhibit changes (Stone et al., 1992; Strettoi et al., 2002). Determining the nature of these changes is critical to understanding the disease process as well as developing treatments.KeywordsRetinitis PigmentosaBipolar CellAmacrine CellInner Nuclear LayerRetinal DystrophyThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Autologous transplantation of genetically modified iris pigment epithelial cells: a promising concept for the treatment of age-related macular degeneration and other disorders of the eye.

Age-related macular degeneration (ARMD) is the leading cause for visual impairment and blindness in the elder population. Laser photocoagulation, photodynamic therapy and excision of neovascular membranes have met with limited success. Submacular transplantation of autologous iris pigment epithelial (IPE) cells has been proposed to replace the damaged retinal pigment epithelium following surgical removal of the membranes. We tested our hypothesis that the subretinal transplantation of genetically modified autologous IPE cells expressing biological therapeutics might be a promising strategy for the treatment of ARMD and other retinal disorders. Pigment epithelium-derived factor (PEDF) has strong antiangiogenic and neuroprotective activities in the eye. Subretinal transplantation of PEDF expressing IPE cells inhibited pathological choroidal neovascularization in rat models of laser-induced rupture of Bruch's membrane and of oxygen induced ischemic retinopathy. PEDF expressing IPE transplants also increased the survival and preserved rhodopsin expression of photoreceptor cells in the RCS rat, a model of retinal degeneration. These findings suggest a promising concept for the treatment of ARMD and other retinal disorders.

Preservation of visual responsiveness in the superior colliculus of RCS rats after retinal pigment epithelium cell transplantation

The dystrophic RCS rat undergoes progressive photoreceptor degeneration due to a primary defect in retinal pigment epithelial (RPE) cells. This has a major impact on central visual responsiveness. Here we have examined how functional deterioration is contained by subretinal transplantation of immortalized human RPE cells. Transplantation was done at three to four weeks of age prior to significant photoreceptor loss and recipients were kept on cyclosporin. At six months of age, sensitivity maps and multi-unit response properties were obtained across the visual field by recording at 76 equidistant sites encompassing the whole superior colliculus. A significant degree of functional protection, both in terms of area of responsive retina and response characteristics was observed following RPE transplantation. At best, the sensitivity, latency of onset, and response rise time were all maintained within normal ranges and this was achieved with no more than half of the normal complement of photoreceptors. Although partial, the degree of anatomical preservation (both in terms of outer nuclear layer thickness and area of rescue) correlated well with the level of preserved visual sensitivities. Sham injections also resulted in rescue, though the area of preservation was strictly confined to the needle injury site and the response properties were significantly worse than with RPE injections. This study shows that central physiological responsiveness and correlated retinal morphology can be preserved in an animal model of retinal disease by implantation of an immortalized cell line. The use of retinal sensitivity measurements provides a background for assessing higher visual functions in these animals and a direct comparison for human perimetry measures.

Subretinal Transplantation of Brain-derived Precursor Cells to Young RCS Rats Promotes Photoreceptor Cell Survival☆

The potential use of in vitro-expanded precursor cells or cell lines in brain repair includes transplantation of such cells for cell replacement purposes and the activation of host cells to provide ‘self-repair’. Recently, it has been reported that the immortalized brain-derived cell line RN33B (derived from the embryonic rat medullary raphe) survive, integrate and differentiate after subretinal grafting to normal adult rats. Here, it is demonstrated that grafts of these cells survive for at least 6 weeks after implantation into postnatal days 21 and 35 retinas of normal and Royal College of Surgeons rats, a model of retinal degeneration. Implanted cells integrate into the retinal pigment epithelium and the inner retinal layers, and the anterior part of the optic nerve of both normal and Royal College of Surgeons rats. The RN33B cells migrate within the retina, occupying the whole retina from one eccentricity to the other. A significant number of the grafted cells differentiate into glial cells, as shown by the double labelling of the reporter genes LacZ or green fluorescent protein, with several glial markers, including oligodendrocytic markers. Many implanted cells in the host retina were in a proliferative stage judging from proliferative cell nuclear antigen and SV40 large T-antigen immunohistochemistry. Interestingly, there was a promotion of photoreceptor survival, extending over more than 2/3 of the superior hemisphere, in Royal College of Surgeons rats transplanted at postnatal day 21, but not at postnatal day 35. In addition, grafted cells were found in the surviving photoreceptor layer in these rats.

Retinal Neuronal Cell Death: Molecular Mechanism and Neuroprotection

In retinitis pigmentosa, retinal detachment, age-related macular degeneration, and glaucoma, retinal neuronal cells are damaged by a common mechanism, apoptosis. Because apoptosis is an active process that requires de novo expression of a "death message", this process can be controlled by inhibiting the expression of the "death message". We first studied whether a retinal ischemia-reperfusion model can be used as a model for retinal neuronal apoptosis. In the retinal ischemia-reperfusion injuries, typical features of apoptosis, including TUNEL-positive cells, DNA ladder formation, and ultrastructural features of apoptosis were found. Using the model, systematic research to identify the "death message" was done by DNA microarray analysis. About 200 messages were found to be up- or down-regulated during the process of retinal ischemia-reperfusion. These genes were divided into four groups: (1) transcription factor genes, (2) cell cycle-related genes, (3) reactive oxygen scavenger genes and (4) molecular chaperon genes. The possible roles of such genes in neuronal apoptosis following retinal ischemia-reperfusion injury were studied. In the model, reactive oxygen species produced by reperfusion was found to generate lipid peroxides and induced up-regulation of a transcription factor, c-Jun, that further induced aberrant expression of cell cycle-related genes such as cyclin D1 in amacrine cells. However, because no controlled expression of cell cycle-related genes takes place in retinal neurons, amacrine cells died by a G1 arrest mechanism. On the other hand, horizontal cells never expressed cyclin D1 and the cells were found to die by necrosis. The study revealed a possible mechanism of retinal neuronal apoptosis and it also became apparent that different types of neurons use different "death messages". Furthermore, the possibility that inhibition of a "death message" sometimes induces necrosis rather than apoptosis was shown. This means that we need to try inhibition of the death mechanism upstream rather than downstream. Administration of thioredoxin, an endogenous reactive oxygen species that blocks generation of lipid peroxides and thus inhibits the death process upstream, was found to be neuroprotective against retinal ischemia-reperfusion injury. Aberrant expression of c-Jun and cyclin D1 was down-regulated by the treatment. Possible roles of caspases were also studied by using the ischemia-reperfusion injury, RCS rat, and excessive light exposure damage in wild type and caspase-1 deficient mice. Also, application of adeno-associated virus that carries Bcl-xL was tested to find possible neuroprotective effects on RCS rats. Our studies showed that caspase-1 played a more important role in the retinal photoreceptors and caspase-3 was important in neurons in the inner nuclear layer. Caspase-2 was found to be a major caspase in the retinal ganglion cell layer. In agreement with the findings, caspase-1 deficient mice showed less prominent light damage than wild type mice. Gene therapy by Bcl-xL was effective to protect retinal photoreceptor damage in RCS rats.

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

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.

Photoreceptor rescue after low-dose intravitreal IL-1β Injection in the RCS Rat

Photoreceptor survival in the dystrophic rat was evaluated following administration of IL-1β at dosages much lower than those used previously for this purpose. Royal College of Surgeons rats (pink-eyed, pigmented, or non-dystrophic) received 1μ l intravitreal injections of murine recombinant IL-1β (0.5, 2, or 5μ gml−1; at 3 or 4 weeks of age). Eyes were harvested 4 weeks later and outer nuclear layer profiles counted. Additional animals received intravitreal basic fibroblast growth factor (1000μ gml−1), or vehicle alone. Others were treated with IL-1β to evaluate the inflammatory response (CD45+ profiles) or visual function via opto-kinetic response. IL-1β was associated with photoreceptor rescue that was both dose-dependent and comparable to that seen following high-dose basic fibroblast growth factor. Significant anatomical rescue relative to controls was seen in both pink-eyed and pigmented strains, although the degree and distribution varied between strains. Functional rescue was confirmed by opto-kinetic response using the pigmented strain. At 5μ gml−1, IL-1β resulted in numerous CD45+ profiles within the retina and vitreous. Infiltration peaked at 48hr and was minimal at 4 weeks, without dysplastic sequelae. IL-1β therefore induces visually significant photoreceptor rescue in a potent, dose-dependent manner that need not entail cytoarchitectural disruption. This is consistent with the known association between injury and rescue in the rat retina. Neuroprotection may be a general, if under-appreciated, consequence of inflammatory cascade activation.

Lens epithelium-derived growth factor (LEDGF) delays photoreceptor degeneration in explants of rd/rd mouse retina.

Lens epithelium derived growth factor (LEDGF) has been shown to rescue embryonic chick photoreceptor cells from serum starvation and heat stress, light damaged photoreceptor cells in Lewis rats, and photoreceptor cells in RCS rats. The aim of our study is to study the rescue effect of LEDGF on photoreceptor cells in the rd/rd mouse using our long-term serum free organ culture. At the end of this culture period of 21-26 days LEDGF treated rd mouse retina showed an increased photoreceptor survival compared to the untreated controls. LEDGF has no effect on expression and localization of opsin and arrestin in the rod photoreceptor cells when RPE is present. The protective potency of LEDGF on the retinal photoreceptor cells is similar to that of BDNF. LEDGF is known to activate heat shock proteins (Hsps) and the elevated Hsps are also reported to suppress apoptosis.

Electrophysiological properties of rat retinal Müller (glial) cells in postnatally developing and in pathologically altered retinae.

Retinal glial Müller cells are characterized by dominant K(+) conductances. The cells may undergo changes of their membrane currents during ontogeny and gliosis as described in rabbit and man. Although the rat retina is often used in physiological experiments, the electrophysiology of rat Müller cells is less well studied. The aim of the present study was to characterize their membrane currents in postnatal development and in two models of retinal degeneration. Freshly isolated cells were subjected to whole-cell patch clamp recordings. During the first 4 weeks after birth of rats, their Müller cells displayed an increase in all membrane currents, particularly in the inward currents elicited at hyperpolarizing potentials. The decrease of the membrane resistance from more than 760 MOmega to less than 50 MOmega was accompanied by a shift of the zero current potential from about -20 mV to -80 mV, similar as earlier observed in developing rabbit Müller cells. These developmental changes were found in pigmented Brown Norway rats as well as in rats with inherited retinal dystrophy (RCS rats). Moreover, an infection of Lewis rats with the Borna disease virus caused substantial neuroretinal degeneration but did not result in a strong reduction of inward currents and of the zero current potential of the Müller cells. Thus, rat Müller cells fail to change their basic membrane properties in two different models of retinal pathology. This is in contrast to human and rabbit Müller cells, which have been shown to undergo dramatic changes of their membrane physiology in response to retinal diseases and injuries.

Chapter 44 Legacy of the RCS rat: impact of a seminal study on retinal cell biology and retinal degenerative diseases

Chapter 44 Legacy of the RCS rat: impact of a seminal study on retinal cell biology and retinal degenerative diseases

Transplantation of iris pigment epithelium into the choroid slows down the degeneration of photoreceptors in the RCS rat.

Trophic factors [e.g. basic fibroblast growth factor (bFGF)] released by transplanted retinal pigment epithelial (RPE) cells are able to slow down the hereditary degeneration of the retina in the Royal College of Surgeons rat in sites distant from the site of transplantation where rod outer segment (ROS) phagocytic activity is not reconstituted by the transplants. To investigate whether iris pigmented epithelial (IPE) cells are also able to generate this rescue by trophic factors, we transplanted IPE cells from Long-Evans rats into the choroid and subretinal space of 17 young RCS rats. The eyes were enucleated after 6 months and prepared for light microscopy. Six age-matched RCS rats served as controls. Light microscope sections from the whole choroid, healthy choriocapillaris, transplanted cells and the maximum thickness of the choroid, and outer nuclear layer parameters were analyzed by computer-assisted morphometry. In transplanted animals photoreceptor cells were rescued from degeneration although the majority of the transplanted IPE cells were located in the choroid. In the non-transplanted group photoreceptors were absent. Transplantation of IPE cells slows down degeneration of the photoreceptors in the RCS rat. This photoreceptor-sparing effect by the IPE cells was observed even when the transplants were predominantly located within the choroid. The beneficial effect observed may be related to trophic factors possibly secreted by the transplanted IPE cells.

Homozygous Deletion in the Coding Sequence of the c-mer Gene in RCS Rats Unravels General Mechanisms of Physiological Cell Adhesion and Apoptosis

The RCS rat presents an autosomal recessive retinal pigment epithelium dystrophy characterized by the outer segments of photoreceptors being phagocytosis-deficient. A systematic genetic study allowed us to restrict the interval containing the rdy locus to that between the markers D3Mit13 and D3Rat256. We report the chromosomal localization of the rat c-mer gene in the cytogenetic bands 3q35-36, based on genetic analysis and radiation hybrid mapping. Using a systematic biocomputing analysis, we identified two strong related candidate genes encoding protein tyrosine kinase receptors of the AXL subfamily. The comparison of their expression patterns in human and mice tissues suggested that the c-mer gene was the best gene to screen for mutations. RCS rdy− and RCS rdy+ cDNAs were sequenced. The RCS rdy− cDNAs carried a significant deletion in the 5′ part of the coding sequence of the c-mer gene resulting in a shortened aberrant transcript encoding a 20 amino acid peptide. The c-mer gene contains characteristic motifs of neural cell adhesion. A ligand of the c-mer receptor, Gas6, exhibits antiapoptotic properties.

Gene therapy for ocular disease.

Gene therapy for ocular disease.

Regulation of FGF soluble receptor type 1 (SR1) expression and distribution in developing, degenerating, and FGF2-treated retina.

The spatial and temporal patterns of expression and content of the fibroblast growth factor (FGF) soluble receptor SR1, a specific inhibitor of FGF, were investigated during embryonic and postnatal development of the retina in Fisher rats. As early as at embryonic day 18 (E18), SR1 mRNA and protein were detected in the retina. SR1 protein was strongly associated with the differentiating ganglion cells and its distribution paralleled the radial pattern of retinal development, from center to periphery. From E18 to postnatal day 5, the levels of both SR1 mRNA and SR1 protein remained constant. Thereafter, they decreased rapidly, by a factor of 5 in the adult retina. SR1 was labeled in the inner nuclear layer, but never in the photoreceptor nuclei. In the neural retina of RCS dystrophic rats, the levels SR1 mRNA and SR1 protein were 2 to 3 times higher than those in the normal congenic controls, before and during photoreceptor degeneration. These results provide the first evidence that a natural FGF inhibitor is regulated during retina development and degeneration and suggest that changes in SR1 content may be involved in the regulation of FGF activities in retina. This was confirmed in vivo in RCS rats, in which delayed photoreceptor apoptosis by intravitreal injection of FGF2 was accompanied by a downregulation of SR1 expression. Dev Dyn 2000;217:24-36.