Light Damage Models of Retinal Degeneration.

The induction of retinal degeneration by light exposure is widely used to study mechanisms of cell death. The advantage of such light-induced lesions over genetically determined degenerations is that light exposures can be manipulated according to the needs of the experimenter. Bright white light exposure can induce a synchronized burst of apoptosis in photoreceptors in a large retinal area which permits to study cellular and molecular events in a controlled fashion.

Light damage as a model of retinal degeneration.

The induction of retinal degeneration by light exposure is widely used to study mechanisms of cell death. The advantage of such light-induced lesions over genetically determined degenerations is that light exposures can be manipulated according to the needs of the experimenter. Bright white light exposure can induce a synchronized burst of apoptosis in photoreceptors in a large retinal area which permits to study cellular and molecular events in a controlled fashion.

Noninvasive, in vivo assessment of mouse retinal structure using optical coherence tomography.

Background: Optical coherence tomography (OCT) is a novel method of retinal in vivo imaging. In this study, we assessed the potential of OCT to yield histology-analogue sections in mouse models of retinal degeneration.

Methodology/principal Findings: We achieved to adapt a commercial 3(rd) generation OCT system to obtain and quantify high-resolution morphological sections of the mouse retina which so far required in vitro histology.

Cooperative phagocytes: resident microglia and bone marrow immigrants remove dead photoreceptors in retinal lesions.

Phagocytosis is essential for the removal of photoreceptor debris following retinal injury. We used two mouse models, mice injected with green fluorescent protein-labeled bone marrow cells or green fluorescent protein-labeled microglia, to study the origin and activation patterns of phagocytic cells after acute blue light-induced retinal lesions. We show that following injury, blood-borne macrophages enter the eye via the optic nerve and ciliary body and soon migrate into the injured retinal area.

Müller cell response to blue light injury of the rat retina.

Purpose: In addition to photoreceptor degeneration, excessive light causes degenerative alterations in the inner retina and ganglion cell death. A disturbance in osmohomeostasis may be one causative factor for the alterations in the inner retina. Because Müller cells mediate inner retinal osmohomeostasis (mainly through channel-mediated transport of potassium ions and water), the authors investigated whether these cells alter their properties in response to excessive blue light.

Localization of glial aquaporin-4 and Kir4.1 in the light-injured murine retina.

Excessive light causes damage to photoreceptor and pigment epithelial cells, and a local edema in the outer retina. Since Müller glial cells normally mediate the osmohomeostasis in the inner retina (mainly via channel-mediated transport of potassium and water), we determined whether retinal light injury causes an alteration in the retinal localization of glial water (aquaporin-4) and potassium (Kir4.1) channels, and in the potassium conductance of Müller cells.

R91W mutation in Rpe65 leads to milder early-onset retinal dystrophy due to the generation of low levels of 11-cis-retinal.

RPE65 is a retinal pigment epithelial protein essential for the regeneration of 11-cis-retinal, the chromophore of cone and rod visual pigments. Mutations in RPE65 lead to a spectrum of retinal dystrophies ranging from Leber's congenital amaurosis to autosomal recessive retinitis pigmentosa. One of the most frequent missense mutations is an amino acid substitution at position 91 (R91W).

The retinal G protein-coupled receptor (RGR) enhances isomerohydrolase activity independent of light.

Rod and cone visual pigments use 11-cis-retinal, a vitamin A derivative, as their chromophore. Light isomerizes 11-cis- into all-trans-retinal, triggering a conformational transition of the opsin molecule that initiates phototransduction. After bleaching all-trans-retinal leaves the opsin, and light sensitivity must be restored by regeneration of 11-cis-retinal.

Molecular mechanisms of light-induced photoreceptor apoptosis and neuroprotection for retinal degeneration.

Human retinal dystrophies and degenerations and light-induced retinal degenerations in animal models are sharing an important feature: visual cell death by apoptosis. Studying apoptosis may thus provide an important handle to understand mechanisms of cell death and to develop potential rescue strategies for blinding retinal diseases. Apoptosis is the regulated elimination of individual cells and constitutes an almost universal principle in developmental histogenesis and organogenesis and in the maintenance of tissue homeostasis in mature organs.

New retinal light damage QTL in mice with the light-sensitive RPE65 LEU variant.

The purpose of this study was to determine the QTL that influence acute, light-induced retinal degeneration differences between the BALB/cByJ and 129S1/SvImJ mouse strains. Five- to 6-week-old F(2) progeny of an intercross between the two strains were exposed to 15,000 LUX of white light for 1 h after their pupils were dilated, placed in the dark for 16 h, and kept for 10-12 days in dim cyclic light before retinal rhodopsin was measured spectrophotometrically. This was used as the quantitative trait for retinal degeneration.

The genetic modifier Rpe65Leu(450): effect on light damage susceptibility in c-Fos-deficient mice.

Purpose: To test whether introduction of the Rpe65Leu(450) variant can overcome protection against light-induced photoreceptor apoptosis in mice without the activator protein (AP)-1 constituent c-Fos.

Methods: c-Fos-deficient mice (c-fos(-/-)) carrying the Leu(450) variant of RPE65 were compared with c-fos(-/-) mice with Rpe65Met(450). Expression of RPE65 was analyzed by Western blot analysis.

Evidence for two apoptotic pathways in light-induced retinal degeneration.

Excessive phototransduction signaling is thought to be involved in light-induced and inherited retinal degeneration. Using knockout mice with defects in rhodopsin shut-off and transducin signaling, we show that two different pathways of photoreceptor-cell apoptosis are induced by light. Bright light induces apoptosis that is independent of transducin and accompanied by induction of the transcription factor AP-1.

HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration.

Erythropoietin (Epo) is upregulated by hypoxia and provides protection against apoptosis of erythroid progenitors in bone marrow and brain neurons. Here we show in the adult mouse retina that acute hypoxia dose-dependently stimulates expression of Epo, fibroblast growth factor 2 and vascular endothelial growth factor via hypoxia-inducible factor-1alpha (HIF-1alpha) stabilization. Hypoxic preconditioning protects retinal morphology and function against light-induced apoptosis by interfering with caspase-1 activation, a downstream event in the intracellular death cascade.

Fra-1 substitutes for c-Fos in AP-1-mediated signal transduction in retinal apoptosis.

Lack of the AP-1 member c-Fos protects photoreceptors against light-induced apoptosis, a model for retinal degeneration. In mice, light damage increases the activity of the transcription factor AP-1, while pharmacological suppression of AP-1 prevents apoptosis, suggesting the involvement of pro-apoptotic AP-1 target genes. Recently, however, it was shown that photoreceptors expressing Fra-1 in place of c-Fos (Fos (Fosl1/Fosl1) ) are apoptosis competent despite the lack of transactivation domains in Fra-1.

Localization of organic anion transport protein 2 in the apical region of rat retinal pigment epithelium.

Purpose: The organic anion transporting protein (Oatp)-2 has been cloned from brain and retina. It mediates transport of many endogenous and exogenous amphiphilic compounds across the plasma membrane in a sodium-independent manner. In the brain it resides at the luminal and abluminal membrane of the capillary endothelium and at the basolateral membrane of the choroid plexus epithelium.

Apoptosis in the Retina: The Silent Death of Vision.

Pathogenetic mechanisms of retinal degeneration include cell loss by apoptosis. This gene-regulated mode of single-cell death occurs in a number of widespread human diseases such as neurodegeneration. The knowledge of genes and signaling in retinal apoptosis is expanding and opens up therapeutic strategies to ameliorate blinding retinal diseases.