Comparative light and electron microscopic study of retinal histogenesis in normal and rd mutant mice

Sanyal, S.; Bal, Arya K.

doi:10.1007/bf00519723

Cited by 151 publications

(78 citation statements)

References 31 publications

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“…Such patterns of hypopigmentation, due to a variety of causes including but not limited to RPE cell dropout, have been seen in fundus photographs of most of the known murine inherited retinal degenerations~Hawes et al, 1999;Chang et al, 2002;Mehalow et al, 2003;Pang et al, 2005!. As we have reported here, several studies correlate areas of RPE cell thinning with the apposing and localized loss of photoreceptor cell bodies comprising the ONL~Caley et al, 1972;Sanyal & Bal, 1973;Sanyal et al, 1980;LaVail et al, 1982LaVail et al, , 1993Blanks et al, 1982;Messer et al, 1993!. As in other photoreceptor degenerations, Müller cells fill in space left by these dying photoreceptors. Though immunocytochemistry shows that there is some upregulation of GFAP in these cells, as has been seen in other retinal degenerations~Eisenfeld et al, 1984;Lewis et al, 1994!, we , there is an increase in apoptotic profiles though they are still restricted to the inner retinal layers.…”

Section: Discussionsupporting

confidence: 68%

Morphological characterization of the retinal degeneration in three strains of mice carrying the rd-3 mutation

Fariss

Heckenlively

Farber³

et al. 2005

Vis Neurosci

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Retinal development in 3 strains of rd-3/rd-3 mutant mice, previously shown to have different rates of degeneration, was studied using light, electron, and immunofluorescence microscopy. The time course and phenotype of the degeneration as well as details on the mechanism of massive photoreceptor cell loss are compared with other known retinal degenerations in mice. Up until postnatal day (P) 10, the retinas of all three strains (RBF, 4Bnr, In-30) develop similarly to those of pigmented and nonpigmented controls. TUNEL-positive cells appear in the outer nuclear layer (ONL) by P14, and reach a maximum in all three mutant strains around P21. Scattered rods and cones form a loose, monolayered ONL by 8 weeks in the albino RBF strain, by 10 weeks in the albino 4Bnr strain, and by 16 weeks in the pigmented In-30 strain. Though the initial degeneration begins in the central retina, there is no preferred gradient of cell death between central and peripheral photoreceptors. Rods and cones are present at all ages examined. During development, stacks of outer segments (OS) form in all three strains though they never achieve full adult lengths, and often have disorganized, atypical OS. Rod opsin is expressed in the developing OS but is redistributed into plasma membrane as OS degeneration proceeds. Retinal pigment epithelial (RPE) cells of all mutant strains contain packets of phagocytosed OS, and their apical processes associate with the distal ends of the OS. At their synaptic sites, photoreceptor terminals contain ribbons apposed to apparently normal postsynaptic triads. As photoreceptors are lost, Müller cells fill in space in the ONL but they do not appear to undergo significant hypertrophy or migration, though during the degeneration, glial fibrillary acidic protein (GFAP) expression is gradually upregulated. Macrophage-like cells are found frequently in the subretinal space after the onset of photoreceptor apoptosis. As OS disappear, the RPE apical processes revert to simple microvilli. Late in the degeneration, some RPE cells die and neighboring cells appear to flatten as if to maintain confluence. In regions of RPE cell loss that happen to lie above retina where the ONL is gone, cells of the inner nuclear layer (INL), wrapped by Müller cell processes, may front directly on Bruch's membrane.

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Section: Discussionsupporting

confidence: 68%

Morphological characterization of the retinal degeneration in three strains of mice carrying the rd-3 mutation

Fariss

Heckenlively

Farber³

et al. 2005

Vis Neurosci

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“…These rd1 mice show an early-onset severe retinal degeneration because of a nonsense mutation in the Pde6b gene (Pittler and Baehr, 1991) encoding the ␤ subunit of cGMP-phosphodiesterase. Degeneration becomes evident in the outer segments first as early as postnatal day 8, followed by the inner segments and photoreceptor cell bodies (Sanyal and Bal, 1973). Degeneration occurs so rapidly that only a thin layer of scattered rod photoreceptor cell bodies (lacking outer segments) remains at postnatal day 15, and the rod cell bodies disappear completely from the central retina by 36 d (Caley et al, 1972;Carter-Dawson et al, 1978), leading to blindness.…”

Section: Resultsmentioning

confidence: 99%

3,4-Dihydroxyphenylalanine Reverses the Motor Deficits in Pitx3-DeficientAphakiaMice: Behavioral Characterization of a Novel Genetic Model of Parkinson's Disease

Hwang¹,

Fleming²,

Ardayfio³

et al. 2005

J. Neurosci.

164

156

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Parkinson's disease (PD) is a neurodegenerative disease characterized by a loss of dopaminergic neurons in the substantia nigra. There is a need for genetic animal models of PD for screening and in vivo testing of novel restorative therapeutic agents. Although current genetic models of PD produce behavioral impairment and nigrostriatal dysfunction, they do not reproduce the loss of midbrain dopaminergic neurons and 3,4-dihydroxyphenylalanine (L-DOPA) reversible behavioral deficits. Here, we demonstrate that Pitx3-deficient aphakia (ak) mice, which have been shown previously to exhibit a major loss of substantia nigra dopaminergic neurons, display motor deficits that are reversed by L-DOPA and evidence of "dopaminergic supersensitivity" in the striatum. Thus, ak mice represent a novel genetic model exhibiting useful characteristics to test the efficacy of symptomatic therapies for PD and to study the functional changes in the striatum after dopamine depletion and L-DOPA treatment.

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“…*Significantly higher numbers of host cones in the transplant area of eyes with SC response: versus no surgery (PD 35), P , 0·01; versus no surgery (PD 63-67), P , 0·001; versus sham surgery, P , 0·001; versus outside transplant, P , 0·001; versus transplant area without response, P , 0·001: degenerated, leaving a monolayer of cones, without outer segments (Mohand-Said et al, 2000). The number of remaining cone nuclei slowly declines over the ensuing months (Sanyal and Bal, 1973), followed by a slow remodeling of the inner retina (Strettoi and Pignatelli, 2000;Marc et al, 2003;Strettoi et al, 2003). In this study, recoverin immunochemistry was examined in the host retina of the transplanted and control eyes.…”

Section: Discussionmentioning

confidence: 99%

Restoration of visual responses following transplantation of intact retinal sheets in rd mice

Arai

Thomas

Seiler

et al. 2004

Experimental Eye Research

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Purpose. To correlate the functional outcomes with histologic findings following transplantation of fetal retinal sheets in rd mice, and to investigate the mechanisms of visual function restoration.Methods. Twenty-one postnatal day 31 -38 rd/rd (C3H/HeJ) mice were transplanted in one eye with retinal sheets (1·0 £ 0·4 mm) obtained from embryonic day (E) 17 enhanced-green-fluorescent protein (eGFP) mice. Five mice underwent sham surgery without insertion of tissue. Four to five weeks after transplantation, visual responses to a light flash were recorded across the superior colliculus (SC) in seven eyes of seven transplanted mice that had clear corneas and lenses, and in all five sham surgery mice. Following the SC recording, the eyes were enucleated and processed for immunohistochemistry and examined using confocal microscopy.Results. In three out of the seven eyes (43%), positive responses were recorded in the SC in an area topographically corresponding to the placement of the transplant in the host retina. No responses were recorded in the untreated eyes of 5-week-old and 9-week-old rd/rd mice, and in the 9-week-old sham surgery mice. In contrast, visual responses were recorded over the entire SC in normal eyes. The response onset latencies of the 3 transplanted mice with responses were similar to those of normal control mice. The organization of the graft did not appear to correlate as expected with the electrophysiology results, as eyes with well-organized, laminated grafts showed no response whereas the three light-responsive eyes had rosetted or disorganized grafts. All three light-responsive eyes demonstrated much higher levels of recoverin immunoreactivity in the host retina overlying the graft compared with untreated age-matched rd/rd mice.Conclusion. Restoration of the SC visual response does not appear to depend on a well-organized transplant in the rd mouse. Increased recoverin-staining in the host retina in light-responsive animals suggested that host cone rescue was the likely mechanism of vision restoration in this transplant model. q

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Comparative light and electron microscopic study of retinal histogenesis in normal and rd mutant mice

Cited by 151 publications

References 31 publications

Morphological characterization of the retinal degeneration in three strains of mice carrying the rd-3 mutation

Morphological characterization of the retinal degeneration in three strains of mice carrying the rd-3 mutation

3,4-Dihydroxyphenylalanine Reverses the Motor Deficits in Pitx3-DeficientAphakiaMice: Behavioral Characterization of a Novel Genetic Model of Parkinson's Disease

Restoration of visual responses following transplantation of intact retinal sheets in rd mice

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