Photoreceptor survival-promoting activity in interphotoreceptor matrix preparations: Characterization and partial purification

Hewitt, Alice; Lindsey, James D.; Carbott, D.; Adler, Ruben

doi:10.1016/0014-4835(90)90013-k

Cited by 70 publications

(29 citation statements)

References 24 publications

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“…Other possibilities include changes in the structural and biochemical microenvironment, which are known to induce cone cell degeneration. These changes can be introduced by loss of structural support of neighboring rods due to lack of visual chromophore supplementation or alterations in the interphotoreceptor matrix that contains factors promoting cone survival (40).…”

Section: Discussionmentioning

confidence: 99%

Human cone photoreceptor dependence on RPE65 isomerase

Jacobson

Alemán

Cideciyan

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

135

144

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The visual (retinoid) cycle, the enzymatic pathway that regenerates chromophore after light absorption, is located primarily in the retinal pigment epithelium (RPE) and is essential for rod photoreceptor survival. Whether this pathway also is essential for cone photoreceptor survival is unknown, and there are no data from man or monkey to address this question. The visual cycle is naturally disrupted in humans with Leber congenital amaurosis (LCA), which is caused by mutations in RPE65, the gene that encodes the retinoid isomerase. We investigated such patients over a wide age range (3-52 years) for effects on the cone-rich human fovea. In vivo microscopy of the fovea showed that, even at the youngest ages, patients with RPE65-LCA exhibited cone photoreceptor loss. This loss was incomplete, however, and residual cone photoreceptor structure and function persisted for decades. Basic questions about localization of RPE65 and isomerase activity in the primate eye were addressed by examining normal macaque. RPE65 was definitively localized by immunocytochemistry to the central RPE and, by immunoblotting, appeared to concentrate in the central retina. The central retinal RPE layer also showed a 4-fold higher retinoid isomerase activity than more peripheral RPE. Early cone photoreceptor losses in RPE65-LCA suggest that robust RPE65-based visual chromophore production is important for cones; the residual retained cone structure and function support the speculation that alternative pathways are critical for cone photoreceptor survival.optical coherence tomography ͉ retinal degeneration ͉ retinoid cycle ͉ Leber congenital amaurosis ͉ gene therapy V ertebrate retinas have two types of photoreceptors: rods for the perception of dim light and cones for the perception of bright light. Light absorbed by visual pigments of photoreceptors triggers a series of enzymatic reactions known as phototransduction (1). The light-capturing part of the visual pigment, the chromophore, must then be regenerated. The pathway for regeneration of rhodopsin (the rod visual pigment) is known as the visual (retinoid) cycle (2, 3) and involves both rod cells and the adjacent retinal pigment epithelium (RPE). All-trans-retinal is reisomerized to 11-cis-retinal by a reaction in the RPE that requires the retinal isomerase, retinal pigment epithelium-specific 65-kDa protein (RPE65), and lecithinretinol acyltransferase (LRAT) activities. Functional visual pigment is then reformed by combining the 11-cis-chromophore with the photoreceptor opsin apoprotein (4). Molecular knowledge of the visual cycle has increased as the genes encoding the enzymes of this pathway have been elucidated (2, 5, 6).Decades ago, cone pigment regeneration was proposed to be RPE cell-independent (7, 8). More recently, cone-dominant ground squirrel and chicken retinas have been shown to exhibit retinoid isomerase activity that is distinct from RPE65 (5, 9, 10). Murine double knockout experiments, however, provide evidence that RPE65 and the RPE are essential for cone function (11...

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Section: Discussionmentioning

confidence: 99%

Human cone photoreceptor dependence on RPE65 isomerase

Jacobson

Alemán

Cideciyan

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

135

144

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“…It might have increased the availability of some factor(s) that promotes cone production; diffusible rod-promotive factors have been inferred (Altshuler and Cepko, 1992;Hicks and Courtois, 1992;Watanabe and Raff, 1992), as have cone-promotive extracellular matrix molecules (Hewitt et al, 1990;Hunter et al, 1992). A role for such cone-promotive factors in the anomalous cone production in stretched retina cannot be ruled out, yet we each with an accessory outer segment (A) and calical processes (arrows).…”

Section: Neurogenesismentioning

confidence: 91%

Cone photoreceptor regeneration in adult fish retina: phenotypic determination and mosaic pattern formation

Cameron

Easter

1995

J. Neurosci.

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The retina of anamniotes (fish and amphibia), unlike the CNS of most vertebrates, can regenerate neurons following injury. Using the highly ordered mosaic of single and double cones in the retina of the adult green sunfish (Lepomis cyanellus) as our model system, we examined the events that followed the surgical excision of a small patch of central retina. After surgery there was a transient elevation in the number, and a change in the distribution, of proliferative cells within the retina. The wound was filled in two ways: a proliferative regeneration of new retina and a nonproliferative movement of the wound boundaries toward the center of the lesion. The nonproliferative movement stretched the surrounding, intact retina. In stretched retina the basic pattern of the cone mosaic was maintained, but it was augmented by new cones, even though cones are not normally generated in intact central retina. The stretch itself likely triggered the anomalous cone production. The new and preexisting cones in stretched retina had their morphological phenotypes influenced by mutual contact, often resulting in atypical morphologies (triple and quadruple cones). In the center of the lesioned area, the regenerated cone mosaic was disordered, had a higher than normal cone density, and contained atypical morphologies. The presence of outer segments and synaptic pedicles suggested that the new cones in regenerated and stretched retina were functional. We interpret these results to mean (1) a stretch-induced decrease in cell density can trigger a compensatory, adaptive neurogenesis, (2) cone morphological phenotypes in fish retina are plastic throughout life, and are influenced by cone-cone contacts, (3) the mechanisms that spatially regulate cone production during normal growth are disrupted regeneration.

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“…Preservation, by the injected factors, of some intact outer segments in most of the rescued retinas indicates that these agents actually protect the cells from damage at an early stage in the injury event. Although the nature of the protective effect against injury and its relation to protection from cell death remain to be worked out for each factor, it has been shown recently that BDNF appears to protect against oxidative stress in an in vitro system by increasing the activity of glutathione reductase (40 (27), and an IGF binding protein (27), as well as an undefined (non-bFGF) survival-promoting factor (49). Mailer glial cells have both high-and low-affinity binding sites for aFGF and bFGF (16,50), and IL-1 is expressed in Miller cells (51).…”

Section: Quantification Of Photoreceptor Rescue and Macrophagementioning

confidence: 99%

Multiple growth factors, cytokines, and neurotrophins rescue photoreceptors from the damaging effects of constant light.

LaVail

Unoki

Yasumura

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

606

395

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Recent demonstrations ofsurvival-promoting activity by neurotrophic agents in diverse neuronal systems have raised the possibility of pharmacological therapy for inherited and degenerative disorders of the central nervous system. We have shown previously that, in the retina, basic fibroblast growth factor delays photoreceptor degeneration in Royal College ofSurgeons rats with inherited retinal dystrophy and that the growth factor reduces or prevents the rapid photoreceptor degeneration produced by constant light in the rat. This light-damage model now provides an efficient way to assess quantitatively the survival-promoting activity in Wivo of a number of growth factors and other molecules. We report here that photoreceptors can be significantly protected from the damaging effects of light by intravitreal injection of eight different growth factors, cytokines, and neurotrophins that typically act through several distinct receptor families. In addition to basic fibroblast growth factor, those factors providing a high degree of photoreceptor rescue include brainderived neurotrophic factor, ciliary neurotrophic factor, interleukin 1fl, and acidic fibroblast growth factor; those with less activity include neurotrophin 3, insulin-like growth factor II, and tumor necrosis factor a; those showing little or no protective effect are nerve growth factor, epidermal growth factor, platelet-derived growth factor, insulin, insulin-like growth factor I, heparin, and laminin. Although we used at least one relatively high concentration ofeach agent (the highest available), it is still possible that other concentrations or factor combinations might be more protective. Injecting heparin along with acidic fibroblast growth factor or basic fibroblast growth factor further enhanced the degree of photoreceptor survival and also suppressed the increased incidence of macrophages produced by either factor, especially basic fibroblast growth factor. These results now provide the impetus for determining the normal function in the retina, mechanism(s) of rescue, and therapeutic potential in human eye diseases for each agent.

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Photoreceptor survival-promoting activity in interphotoreceptor matrix preparations: Characterization and partial purification

Cited by 70 publications

References 24 publications

Human cone photoreceptor dependence on RPE65 isomerase

Human cone photoreceptor dependence on RPE65 isomerase

Cone photoreceptor regeneration in adult fish retina: phenotypic determination and mosaic pattern formation

Multiple growth factors, cytokines, and neurotrophins rescue photoreceptors from the damaging effects of constant light.

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