The spatio-temporal pattern of photoreceptor degeneration in the aged rd / rd mouse retina

Jiménez, Antonio J.; García-Fernández, José M.; González, Beatriz; Foster, RG

doi:10.1007/s004410050579

Cited by 91 publications

(68 citation statements)

References 32 publications

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“…In the rd mouse, a differential effect of the mutation on rods and cones was demonstrated by CarterDawson et al (10,11,19); that is, cones die after rods. This model appears appropriate to test the hypothesis of the dependence of cones on the viability of rods.…”

Section: Introductionmentioning

confidence: 90%

Normal retina releases a diffusible factor stimulating cone survival in the retinal degeneration mouse

Mohand‐Saïd¹,

Deudon-Combe²,

Hicks³

et al. 1998

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

187

123

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The role of cellular interactions in the mechanism of secondary cone photoreceptor degeneration in inherited retinal degenerations in which the mutation specifically affects rod photoreceptors was studied. We developed an organ culture model of whole retinas from 5-week-old mice carrying the retinal degeneration mutation, which at this age contain few remaining rods and numerous surviving cones cocultured with primary cultures of mixed cells from postnatal day 8 normal-sighted mice (C57BL͞6) retinas or retinal explants from normal (C57BL͞6) or dystrophic (C3H͞He) 5-week-old mice. After 7 days, the numbers of residual cone photoreceptors were quantified after specific peanut lectin or anti-arrestin antibody labeling by using an unbiased stereological approach. Examination of organ cultured retinas revealed significantly greater numbers of surviving cones (15-20%) if cultured in the presence of retinas containing normal rods as compared with controls or cocultures with rod-deprived retinas. These data indicate the existence of a diffusible trophic factor released from retinas containing rod cells and acting on retinas in which only cones are present. Because cones are responsible for high acuity and color vision, such data could have important implications not only for eventual therapeutic approaches to human retinal degenerations but also to define interactions between retinal photoreceptor types.Despite recent advances, our understanding of the mechanisms underlying visual malfunction and cell loss in retinitis pigmentosa (RP) has provided few clinically significant clues to improve retinal cell survival (1-3). RP forms a group of inherited photoreceptor dystrophies characterized largely by early features of rod photoreceptor impairment (1, 4). Most identified forms of RP are caused by defects in proteins restricted to rod photoreceptors (5-8). Yet, at various stages of the disease, a loss of the photopic function reflecting degeneration of cone photoreceptors is found consistently (1, 4). Of extreme importance for the patient, cone cell death and its functional consequences appear to be secondary events. No current data exist to account for cone cell death, but observations made on animal models of RP provide arguments for cone survival depending on the presence of rods. In several models with selective elimination of rods, secondary loss of cones is observed (9-11). The cause of rod cell death in these animals, either transgenic or spontaneous mutants, cannot account for direct cone cell loss (9-17). Putative mechanisms of cone cell death include the liberation of endotoxins by degenerating rods, environmental alteration, or deprivation of rod-derived trophic factor(s). Recent studies using chimeras of normal and transgenic mice carrying mutations in rods showed that photoreceptor cell death was diffuse rather than restricted to areas with mutations in rods, providing evidence for a role of cellular interactions between photoreceptors in survival and degeneration of these cells (18). Based on these dat...

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Section: Introductionmentioning

confidence: 90%

Normal retina releases a diffusible factor stimulating cone survival in the retinal degeneration mouse

Mohand‐Saïd¹,

Deudon-Combe²,

Hicks³

et al. 1998

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

187

123

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“…We used retinas from mPer2 Luc mice that were homozygous for rd and were 85 Ϯ 2 days old. At this age, virtually all photoreceptors have degenerated in the retinas of mice homozygous for rd (5,(32)(33)(34). Retinas were explanted onto membranes, and luminescence from the PER2::LUC fusion protein was continuously measured in real-time in constant darkness at 36.8°C.…”

Section: Coordinate Expression Of Core Clock Genes Occurs Preferentiamentioning

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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“…In the retinal degeneration rd-1/rd-1 (RD) mouse, rod and cone photoreceptors progressively die in the first weeks after birth, leading eventually to the severe changes in cellular architecture and remodeled neural circuitry that characterize retinal degeneration (Blanks et al, 1974;Carter-Dawson et al, 1978;Jimenez et al, 1996;Strettoi and Pignatelli, 2000;Punzo and Cepko, 2007). Little is known about the functional adaptations that accompany these morphological changes.…”

Section: Introductionmentioning

confidence: 99%

Functional Stability of Retinal Ganglion Cells after Degeneration-Induced Changes in Synaptic Input

Margolis¹,

Newkirk²,

Euler³

et al. 2008

Journal of Neuroscience

197

262

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Glutamate released from photoreceptors controls the activity and output of parallel pathways in the retina. When photoreceptors die because of degenerative diseases, surviving retinal networks are left without their major source of input, but little is known about how photoreceptor loss affects ongoing synaptic activity and retinal output. Here, we use patch-clamp recording and two-photon microscopy to investigate morphological and physiological properties of identified types of ON and OFF retinal ganglion cells (RGCs) in the adult (36 -210 d old) retinal degeneration rd-1/rd-1 mouse. We find that strong rhythmic synaptic input drives ongoing oscillatory spike activity in both ON and OFF RGCs at a fundamental "beating" frequency of ϳ10 Hz. Despite this aberrant activity, ON and OFF cells maintain their characteristic dendritic stratification, intrinsic firing properties, including rebound firing in OFF cells, balance of synaptic excitation and inhibition, and dendritic calcium signaling. Thus, RGCs are inherently stable during degeneration-induced retinal activity.

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The spatio-temporal pattern of photoreceptor degeneration in the aged rd / rd mouse retina

Cited by 91 publications

References 32 publications

Normal retina releases a diffusible factor stimulating cone survival in the retinal degeneration mouse

Normal retina releases a diffusible factor stimulating cone survival in the retinal degeneration mouse

Circadian organization of the mammalian retina

Functional Stability of Retinal Ganglion Cells after Degeneration-Induced Changes in Synaptic Input

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