Apoptotic photoreceptor cell death in mouse models of retinitis pigmentosa.

Portera‐Cailliau, Carlos; Sung, Ching Hwa; Nathans, Jeremy; Adler, Ruben

doi:10.1073/pnas.91.3.974

Cited by 540 publications

(342 citation statements)

References 19 publications

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“…Thus, it would be of value to analyse the presence of IAP proteins and analogs in RPE cells during serum deprivation. Previous studies have suggested that endogenous FGFs act as protection factors in vivo by showing a dramatic upregulation of FGF gene expression in response to cell death in various retinal degeneration models (Portera-Gailleau et al, 1994;Gao and Holly®eld, 1996). We have con®rmed that this is the case in retina, by demonstrating that inhibition of the binding of endogenous FGFs to their receptors accelerates and increases retinal cell apoptosis (Guillonneau et al, 1998a).…”

Section: Discussionmentioning

confidence: 53%

Both FGF1 and Bcl-x synthesis are necessary for the reduction of apoptosis in retinal pigmented epithelial cells by FGF2: role of the extracellular signal-regulated kinase 2

Bryckaert

Guillonneau²,

Hecquet³

et al. 1999

Oncogene

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Retinal pigmented epithelial (RPE) cells are of central importance in the maintenance of neural retinal function. Changes in the RPE cells associated with repair activities have been described as metaplasia, while RPE cell apoptosis is responsible for the development of a variety of retinal degenerations. We investigated the regulation of the anti-apoptotic properties of the ®broblast growth factors (FGF) 2 in serum-free cultures of RPE cells. In the absence of serum, con¯uent stationary RPE cells died by apoptosis via a caspase 3-dependent pathway. The addition of FGF2 greatly reduced apoptosis over a 7-day culture period. We demonstrated the involvement of an autocrine loop involving endogenous FGF1 in the mechanisms that govern FGF2-induced resistance to apoptosis by showing: (1) higher levels of apoptosis in cells treated with antisense FGF1 oligonucleotide or after neutralization of excreted FGF1; (2) the long-term activation of FGFR1 and of ERK2, (3) the inhibition of FGFR1 and ERK2 activation and an increase in apoptosis if excreted FGF1 was neutralized. FGF2 also increased the de novo synthesis and the production of Bcl-xl before the onset of apoptosis. Both inhibition of ERK2 activation, which decreased Bcl-xl synthesis, and downregulation of Bcl-x by antisense oligonucleotide treatment inhibited the survival-promoting activity of FGF2. Thus, FGF2-induced cell survival is a progressive adaptive phenomenon involving ERK2 activation by excreted FGF1 and ERK2-dependent Bcl-x production.

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Section: Discussionmentioning

confidence: 53%

Both FGF1 and Bcl-x synthesis are necessary for the reduction of apoptosis in retinal pigmented epithelial cells by FGF2: role of the extracellular signal-regulated kinase 2

Bryckaert

Guillonneau²,

Hecquet³

et al. 1999

Oncogene

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“…Unlike the rod photoreceptors of the Rds/Rds mouse~Sanyal & Jansen, 1981!, all three strains of the rd-3 homozygotes clearly are able to assemble OS discs, although they are not all normal in either size or orientation. In considering the overall pattern of cell loss, the rd-3/rd-3 degeneration shows no apparent preference for rods over cones or for center versus periphery and thus differs from the rd/rd mouse where rods are lost The TUNEL data show that photoreceptors die by apoptosis in this mutation as in every other retinal degeneration described to date, whether inherited~Chang et al, 1993b; Portera-Cailliau et al, 1994;Tso et al, 1994;Smith et al, 1995;Ikeda et al, 1999;Guarneri et al, 2004!, or induced~Shahinfar et al, 1991Cook et al, 1995!. In the murine retinal degenerations described above, the developmental stage at which the effect of the mutant genes becomes expressed varies widely. The earlier the onset, as in rd, the less mature the OS will be as photoreceptor cells begin to die en masse.…”

Section: Discussionmentioning

confidence: 93%

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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“…18,19 At the same time, calpains directly proteolyse executioner caspases, mediating their activation, 20,21 as well as proapoptotic Bcl-2 family members that eventually cause the release of apoptogenic factors from the mitochondria involved in the triggering of the caspase cascade. [22][23][24] While the time course of developmental apoptosis in the mouse retina has been extensively described in several studies, 10,[25][26][27] the biochemical death pathways involved are not fully understood. In particular, relatively little is known about the molecular mechanisms of developmental apoptosis in cone photoreceptors, due to the paucity of cone-specific markers at early stages of development.…”

Section: Introductionmentioning

confidence: 99%

Multiple death pathways in retina-derived 661W cells following growth factor deprivation: crosstalk between caspases and calpains

2005

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During development of the mammalian retina, neurons that do not succeed in establishing functional synaptic connections are eliminated by apoptosis, allowing the formation of a finely tuned network. Growth factors play a crucial role in controlling the balance between apoptosis and survival signals not only at developmental stages but also in longterm preservation of retinal functions. In the present work, we explore the apoptotic mechanisms triggered by growth factor deprivation of retina-derived 661W cells. Under serum starvation conditions, these cone photoreceptors underwent cell death with participation of caspase-9, -3 and -12. Interestingly, inhibition of caspases did not prevent apoptosis but only resulted in a temporary delay. We show m-calpain activation in parallel with caspases, indicating that more than one execution pathway is available to cone photoreceptors. Moreover, crosstalk of the caspase and calpain pathways was detected, suggesting a loop that may act to amplify the apoptotic cascade.

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Apoptotic photoreceptor cell death in mouse models of retinitis pigmentosa.

Abstract: Retinitis pnentsa (RP)

Cited by 540 publications

References 19 publications

Both FGF1 and Bcl-x synthesis are necessary for the reduction of apoptosis in retinal pigmented epithelial cells by FGF2: role of the extracellular signal-regulated kinase 2

Both FGF1 and Bcl-x synthesis are necessary for the reduction of apoptosis in retinal pigmented epithelial cells by FGF2: role of the extracellular signal-regulated kinase 2

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

Multiple death pathways in retina-derived 661W cells following growth factor deprivation: crosstalk between caspases and calpains

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