Susceptibility to Retinal Light Damage in Transgenic Rats with Rhodopsin Mutations

Organisciak, Daniel T.; Darrow, Ruth M.; Barsalou, Linda; Kutty, R. Krishnan; Wiggert, Barbara

doi:10.1167/iovs.02-0708

Cited by 106 publications

(105 citation statements)

References 20 publications

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“…Light Stress Induces Caspase-3 Activation in IR Knock-out Mouse Retinas-Bright light exposure causes rod photoreceptor death by apoptosis (36,37). Our light stress experiments clearly indicate that IR knock-out mice are more susceptible to bright light-induced photoreceptor degeneration.…”

Section: Effect Of Ir On Retinal Structure After Light Stress-mentioning

confidence: 63%

Loss of Neuroprotective Survival Signal in Mice Lacking Insulin Receptor Gene in Rod Photoreceptor Cells

Rajala

Tanito

et al. 2008

Journal of Biological Chemistry

113

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Insulin receptor (IR) signaling provides a trophic signal for transformed retinal neurons in culture, but the role of IR activity in vivo is unknown. We previously reported that light causes increased tyrosine phosphorylation of the IR in vivo, which leads to the downstream activation of the phosphoinositide 3-kinase and Akt pathway in rod photoreceptor cells. The functional role of IR in rod photoreceptor cells is not known. We observed that light stress induced tyrosine phosphorylation of the IR in rod photoreceptor cells, and we hypothesized that IR activation is neuroprotective. To determine whether IR has a neuroprotective role on rod photoreceptor cells, we used the Cre/lox system to specifically inactivate the IR gene in rod photoreceptors. Rodspecific IR knock-out mice have reduced the phosphoinositide 3-kinase and Akt survival signal in rod photoreceptors. The resultant mice exhibited no detectable phenotype when they were raised in dim cyclic light. However, reduced IR expression in rod photoreceptors significantly decreased retinal function and caused the loss of photoreceptors in mice exposed to bright light stress. These results indicate that reduced expression of IR in rod photoreceptor cells increases their susceptibility to lightinduced photoreceptor degeneration. These data suggest that the IR pathway is important for photoreceptor survival and that activation of the IR may be an essential element of photoreceptor neuroprotection. Insulin receptor (IR)2 signaling provides a trophic signal for transformed retinal neurons in culture (1), but the role of the IR in vivo is unknown. IR activation has been shown to rescue retinal neurons from apoptosis through a phosphoinositide 3-kinase (PI3K) cascade (1). We previously reported that light induces tyrosine phosphorylation of the retinal IR and that this activation leads to the binding of PI3K to rod outer segment (ROS) membranes (2). More recently, we demonstrated that IR activation is mediated through the G-protein-coupled receptor rhodopsin (3). IR signaling is also involved in 17␤-estradiolmediated neuroprotection in the retina (4). Recent evidence suggests a down-regulation of IR kinase activity in diabetic retinopathy that is associated with the deregulation of downstream signaling molecules (5). Deletion of several downstream effector molecules of the IR signaling pathway, such as IRS-2 (6), Akt2 (7), and Bcl-xl (8), in the retina resulted in a photoreceptor degeneration phenotype. These studies clearly indicate the importance of the IR signaling pathway in the retina.The IR is highly conserved, and the high degree of IR signaling homology between Caenorhabditis elegans, Drosophila, and humans suggests functional conservation in mammalian retina. The IR regulates neuronal survival in C. elegans (9). In Drosophila, the IR serves an important function to guide retinal photoreceptor axons from the retina to the brain during development (10), and the IR influences the size and number of photoreceptors (11). The lack of IR activation leads to neurod...

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Section: Effect Of Ir On Retinal Structure After Light Stress-mentioning

confidence: 63%

Loss of Neuroprotective Survival Signal in Mice Lacking Insulin Receptor Gene in Rod Photoreceptor Cells

Rajala

Tanito

et al. 2008

Journal of Biological Chemistry

113

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“…Moreover, the vast majority of mutant rhodopsin colocalizes with calnexin, indicating ER retention caused by misfolding . However, in other animal models expressing murine and human P23H, rod death is exacerbated by light exposure, and the mutant protein is found in the ROS (Naash et al, 1996;Organisciak et al, 2003). Because differences in the primary sequence of rhodopsins of different species could lead to subtle variations in folding and protein stability, we compared the characteristics of wild-type and P23H X. laevis, murine, bovine, and human rhodopsins in transgenic X. laevis retinas.…”

Section: Resultsmentioning

confidence: 99%

“…Our previous study of transgenic Xenopus laevis expressing frog P23H rhodopsin established that the mutant protein was predominantly confined to the ER, with no effect of dark rearing or disruption of visual transduction on the rate of RD . However, in other animal models, P23H rhodopsin traffics normally to the ROS, and RD is exacerbated by light (Naash et al, 1996;Organisciak et al, 2003;Galy et al, 2005). In humans, light may also affect disease progression caused by the rhodopsin mutations T17M and P23H, where the lower retina, which is exposed to brighter illumination from above, is preferentially affected (Li et al, 1994;Cideciyan et al, 1998) Therapy for P23H rhodopsin-induced RP poses a challenge because of its autosomal dominant nature.…”

Section: Introductionmentioning

confidence: 99%

Dark Rearing Rescues P23H Rhodopsin-Induced Retinal Degeneration in a TransgenicXenopus laevisModel of Retinitis Pigmentosa: A Chromophore-Dependent Mechanism Characterized by Production of N-Terminally Truncated Mutant Rhodopsin

Tam¹,

Moritz²

2007

J. Neurosci.

100

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To elucidate the molecular mechanisms underlying the light-sensitive retinal degeneration caused by the rhodopsin mutation P23H, which causes retinitis pigmentosa (RP) in humans, we expressed Xenopus laevis, bovine, human, and murine forms of P23H rhodopsin in transgenic X. laevis rod photoreceptors. All P23H rhodopsins caused aggressive retinal degeneration associated with low expression levels and retention of P23H rhodopsin in the endoplasmic reticulum (ER), suggesting involvement of protein misfolding and ER stress. However, light sensitivity varied dramatically between these RP models, with complete or partial rescue by dark rearing in the case of bovine and human P23H rhodopsin, and no rescue for X. laevis P23H rhodopsin. Rescue by dark rearing required an intact 11-cis-retinal chromophore binding site within the mutant protein and was associated with truncation of the P23H rhodopsin N terminus. This yielded an abundant nontoxic ϳ27 kDa form that escaped the ER and was transported to the rod outer segment. The truncated protein was produced in the greatest quantities in dark-reared retinas expressing bovine P23H rhodopsin and was not observed with X. laevis P23H rhodopsin. These results are consistent with a mechanism involving enhanced protein folding in the presence of 11-cis-retinal chromophore, with ER exit assisted by proteolytic truncation of the N terminus. This study provides a molecular mechanism for light sensitivity observed in other transgenic models of RP and for phenotypic variation among RP patients.

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“…The retinal circadian clock and its dopamine-and melatonin-signaling molecules also influence pathological processes in the eye, including the susceptibility of photoreceptors to degeneration from light damage (15,16), photoreceptor survival in animal models of retinal degeneration (17), and the degree of refractive errors in primate models of myopia (18). Despite its widespread influence, the cellular origin and organization of the circadian clock in the mammalian retina remain unclear.…”

mentioning

confidence: 99%

Circadian organization of the mammalian retina

Ruan

Zhang

Zhou

et al. 2006

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

149

185

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The mammalian retina contains an endogenous circadian pacemaker that broadly regulates retinal physiology and function, yet the cellular origin and organization of the mammalian retinal circadian clock remains unclear. Circadian clock neurons generate daily rhythms via cell-autonomous autoregulatory clock gene networks, and, thus, to localize circadian clock neurons within the mammalian retina, we have studied the cell type-specific expression of six core circadian clock genes in individual, identified mouse retinal neurons, as well as characterized the clock gene expression rhythms in photoreceptor degenerate rd mouse retinas. Individual photoreceptors, horizontal, bipolar, dopaminergic (DA) amacrines, catecholaminergic (CA) amacrines, and ganglion neurons were identified either by morphology or by a tyrosine hydroxylase (TH) promoter-driven red fluorescent protein (RFP) fluorescent reporter. Cells were collected, and their transcriptomes were subjected to multiplex single-cell RT-PCR for the core clock genes Period (Per) 1 and 2, Cryptochrome (Cry) 1 and 2, Clock, and Bmal1. Individual horizontal, bipolar, DA, CA, and ganglion neurons, but not photoreceptors, were found to coordinately express all six core clock genes, with the lowest proportion of putative clock cells in photoreceptors (0%) and the highest proportion in DA neurons (30%). In addition, clock gene rhythms were found to persist for >25 days in isolated, cultured rd mouse retinas in which photoreceptors had degenerated. Our results indicate that multiple types of retinal neurons are potential circadian clock neurons that express key elements of the circadian autoregulatory gene network and that the inner nuclear and ganglion cell layers of the mammalian retina contain functionally autonomous circadian clocks.circadian clock ͉ clock gene ͉ mouse retina ͉ photoreceptor ͉ real-time PCR T he mammalian retinal circadian clock exerts extensive control over retinal physiology and function, regulating a wide variety of retinal circadian rhythms, including rod disk shedding (1-3), melatonin release (4-6), dopamine synthesis (7, 8), electroretinogram (ERG) b-wave amplitude (9), extracellular pH (10), visual sensitivity (11, 12), and intraocular pressure (13,14). The retinal circadian clock and its dopamine-and melatonin-signaling molecules also influence pathological processes in the eye, including the susceptibility of photoreceptors to degeneration from light damage (15, 16), photoreceptor survival in animal models of retinal degeneration (17), and the degree of refractive errors in primate models of myopia (18). Despite its widespread influence, the cellular origin and organization of the circadian clock in the mammalian retina remain unclear.Neural circadian clocks generate endogenous circadian rhythms through cell-autonomous autoregulatory transcriptiontranslation feedback loops comprised of a defined set of ''clock genes'' in subsets of circadian pacemaker neurons. Gene targeting has demonstrated that, in mammals, the genes Period (Per) 1 and 2 and Cr...

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Susceptibility to Retinal Light Damage in Transgenic Rats with Rhodopsin Mutations

Cited by 106 publications

References 20 publications

Loss of Neuroprotective Survival Signal in Mice Lacking Insulin Receptor Gene in Rod Photoreceptor Cells

Loss of Neuroprotective Survival Signal in Mice Lacking Insulin Receptor Gene in Rod Photoreceptor Cells

Dark Rearing Rescues P23H Rhodopsin-Induced Retinal Degeneration in a TransgenicXenopus laevisModel of Retinitis Pigmentosa: A Chromophore-Dependent Mechanism Characterized by Production of N-Terminally Truncated Mutant Rhodopsin

Circadian organization of the mammalian retina

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