• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Feb 23, 2010; 107(8): 3817–3822.
Published online Feb 3, 2010. doi:  10.1073/pnas.0909276107
PMCID: PMC2840442
Neuroscience

ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75NTR non-cell-autonomous signaling pathway

Abstract

Neurotrophin binding to the p75 neurotrophin receptor (p75NTR) activates neuronal apoptosis following adult central nervous system injury, but the underlying cellular mechanisms remain poorly defined. In this study, we show that the proform of nerve growth factor (proNGF) induces death of retinal ganglion cells in adult rodents via a p75NTR-dependent signaling mechanism. Expression of p75NTR in the adult retina is confined to Müller glial cells; therefore we tested the hypothesis that proNGF activates a non-cell-autonomous signaling pathway to induce retinal ganglion cell (RGC) death. Consistent with this, we show that proNGF induced robust expression of tumor necrosis factor alpha (TNFα) in Müller cells and that genetic or biochemical ablation of TNFα blocked proNGF-induced death of retinal neurons. Mice rendered null for p75NTR, its coreceptor sortilin, or the adaptor protein NRAGE were defective in proNGF-induced glial TNFα production and did not undergo proNGF-induced retinal ganglion cell death. We conclude that proNGF activates a non-cell-autonomous signaling pathway that causes TNFα-dependent death of retinal neurons in vivo.

The four mammalian neurotrophins comprise a family of related secreted factors that are required for differentiation, survival, development, and death of specific populations of neurons and nonneuronal cells. Neurotrophins are produced as proforms of ~240 amino acids that are cleaved by furins and proconvertases to yield products of ~120 amino acids. Recent studies have indicated that nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) can be secreted as proforms in the central nervous system (CNS) (1 3) and demonstrated that proneurotrophins can function as potent apoptosis-inducing ligands both in vitro and in vivo (4). However, the precise mechanisms by which proneurotrophins lead to neuronal death are poorly defined.

The biological effects of neurotrophins are mediated by binding to TrkA, TrkB, and TrkC receptor tyrosine kinases and to the p75 neurotrophin receptor (p75NTR). Trk receptors respond preferentially to mature neurotrophins whereas proneurotrophins exert their apoptotic effect via a receptor complex that contains p75NTR and sortilin (5). The precise signaling cascades evoked by occupancy of the p75NTR–sortilin complex remain to be elucidated, but several lines of evidence indicate that NRIF and NRAGE adaptor proteins play key roles in death signaling cascades evoked by p75NTR (6, 7).

Previous studies have shown that neurotrophins induce cell death via p75NTR during early retinal development (8). p75NTR has also been implicated in light-induced photoreceptor death in adult rodents in vivo (9) and a proNGF-p75NTR link has been proposed to facilitate apoptosis in a retinal cell line (10). Here, we investigate the role of proNGF in the adult retina and demonstrate that proNGF promotes death of retinal ganglion cells (RGCs) in vivo. Importantly, proNGF-induced RGC loss is indirect and requires the p75NTR-dependent production of tumor necrosis factor-alpha (TNFα) by Müller glial cells. Therefore, proNGF-induced neuronal loss in the adult retina occurs through a non-cell-autonomous mechanism.

Results

ProNGF Induces Death of Retinal Ganglion Cells in Adult Rodents.

To investigate whether proNGF promotes neuronal death in vivo, we first retrogradely labeled RGCs of adult rats by applying fluorogold to the surface of the superior colliculus and then provided a single intraocular injection of proNGF or vehicle. A week later, retinal whole mounts were prepared and RGC densities were quantified. ProNGF caused a profound loss of adult rat RGCs, whereas vehicle injection had no effect on cell death (Fig. 1A). To determine if the effect of proNGF on neuronal survival was specific to the proform of this neurotrophin, we asked whether mature NGF could similarly promote RGC death and found that neuronal density was not altered by mature NGF treatment (Fig. 1A). The effect of proNGF was not species specific as proNGF also caused a marked loss of RGCs in mice subjected to intraocular proNGF injection (Fig. 1B). We conclude that elevation of proNGF levels within the retina promotes neuronal loss and used this system as a model for examining the cellular details of proNGF-induced cell death in vivo.

Fig. 1.
Exogenous proNGF leads to marked RGC loss in the adult rodent eye. Quantitative analysis is shown of RGC survival in rat (A) and mouse (B) retinas at 1 week after intraocular injection of proNGF (solid bars), vehicle (PBS, shaded bars), or NGF (bars with ...

p75NTR, Sortilin, and NRAGE Are Required for proNGF-Induced Death of Retinal Ganglion Cells.

To determine if p75NTR was required for the loss of RGCs evoked by exogenous proNGF, we first asked whether coinjection of the p75NTR function-blocking antibody REX (11) antagonized proNGF-induced neuronal death. Coadministration of proNGF and REX resulted in significant rescue of RGCs in mice, whereas combined proNGF and nonspecific Ig did not exert a protective effect (Fig. 2A). As an alternative approach, we assessed the apoptotic effect of proNGF in mice deficient for p75NTR and showed that proNGF-induced loss of RGCs did not occur in p75NTR null retinas. Together, these data indicate that proNGF binding to p75NTR is required to induce RGC death.

Fig. 2.
p75NTR, sortilin, and NRAGE are required for proNGF-induced death of RGCs. (A) Treatment with REX, a p75NTR function-blocking antibody, promoted RGC survival in the presence of proNGF whereas coadministration of a nonspecific, control Ig did not exert ...

p75NTR and sortilin have been shown to form a cell surface receptor complex for proneurotrophins that is required for activation of downstream apoptotic pathways (5), and we previously demonstrated that NRAGE, a p75NTR adaptor protein, plays an obligatory role in p75NTR-dependent death (6). We therefore asked whether sortilin or NRAGE was required for proNGF-induced RGC loss in vivo. Our data show that RGCs within sortilin or NRAGE null mice retinas were protected from proNGF-induced death (Fig. 2 C and D). We conclude that p75NTR, sortilin, and NRAGE are each required for proNGF-induced death of RGCs in the adult retina.

ProNGF Kills Retinal Ganglion Cells Through Glia-Mediated Production of TNFα.

A simple model to explain these results would have proNGF binding to the p75NTR–sortilin complex on the surface of RGCs that in turn activates a cell-autonomous, NRAGE-dependent proapoptotic pathway. However, it has been reported that Müller glia are the only cells that express p75NTR in the adult retina (9, 12 15), implying that proNGF killing of RGCs may involve a more complex mechanism. To confirm the p75NTR expression pattern in the adult mouse retina, RGCs were retrogradely labeled with fluorogold and then stained with antibodies specific for p75NTR. In both naive and proNGF-treated animals, RGCs were uniformly negative for p75NTR whereas neighboring cells and processes typical of Müller glia invariably expressed abundant quantities of this receptor (Fig. 3A). Costaining with the Müller cell-specific marker CRALBP confirmed that p75NTR is abundantly expressed by Müller glia, but not RGCs (Fig. 3B). Previous studies have shown that sortilin is expressed by Müller glia in the mouse retina (16), and when we examined the distribution of NRAGE in this system, we found that this p75NTR adaptor protein is abundantly expressed in Müller cell soma and processes (Fig. 3C).

Fig. 3.
p75NTR and p75NTR-induced TNFα are expressed by Müller cells in the adult mouse retina. (A) Confocal microscopy images show absence of p75NTR within Fluorogold-positive RGCs, demonstrating that adult RGCs are devoid of p75NTR. (B) Double ...

On the basis of these results, we hypothesized that proNGF promotes RGC death through an indirect pathway by stimulating the production of a proapoptotic factor by Müller cells. A candidate proapoptotic factor downstream of p75NTR is tumor necrosis factor alpha (TNFα) because exogenous and endogenous TNFα can induce death of retinal neurons (17 19) and because p75NTR activates NF-κB, a transcription complex that is a potent inducer of TNFα production (20 22). To address whether TNFα could play a role in proNGF-induced RGC killing, we first determined if retinal TNFα levels were increased in eyes injected with proNGF. Immunostaining showed that in eyes injected with vehicle or mature NGF, TNFα basal levels were low. In contrast, eyes injected with proNGF showed robust TNFα expression, both in cell bodies in the inner nuclear layer and within processes that extended radially across the breadth of the retina (Fig. 3D). Double immunocytochemistry using antibodies against CRALBP identified these TNFα-expressing cells as Müller glia (Fig. 3E).

The finding that proNGF stimulates TNFα production by Müller cells prompted us to ask whether RGC death induced by this proneurotrophin could be blocked by Etanercept, a recombinant TNFα antagonist in which the extracellular ligand-binding domain of TNFα receptor 2 (TNFR2) is fused to an Fc fragment (23). Fig. 4A shows that intraocular injection of Etanercept markedly blocked RGC death induced by proNGF. To rule out the possibility that Etanercept may have off-target pharmacological effects and to further substantiate a role for TNFα in proNGF-induced killing, we also examined whether proNGF led to RGC loss in TNFα null mice. Our data show that proNGF administration failed to induce RGC death in TNFα null mice (Fig. 4B), indicating that TNFα plays a crucial role in RGC death induced by proNGF.

Fig. 4.
Sortilin and NRAGE cooperate with p75NTR to transduce proNGF-induced signaling events required for TNFα production. (A) Coadministration of proNGF with the TNFα inhibitor Etanercept leads to striking RGC neuroprotection, but RGCs did not ...

These data indicate that proNGF causes RGC death indirectly, by stimulating production of TNFα by Müller glial cells. We therefore tested whether p75NTR and sortilin activated an NRAGE-dependent pathway that resulted in TNFα production. For this purpose, TNFα protein levels were compared in retinas derived from wild-type mice vs. mice lacking p75NTR, sortilin, or NRAGE following proNGF or vehicle injection. In wild-type retinas, robust TNFα protein production was detected within 48 h of proNGF administration, wheras PBS injection had no effect on TNFα levels (Fig. 4C). In contrast, proNGF-induced TNFα up-regulation did not occur in p75NTR, sortilin, and NRAGE null mice (Fig. 4C), correlating with the failure of proNGF to induce RGC death in these null lines (Fig. 2 B–D). Importantly, intraocular injection of TNFα caused RGC death in both wild-type and p75NTR null strains, confirming that TNFα is the actual factor that kills these neurons (Fig. S1). Together, these data indicate that sortilin and NRAGE cooperate with p75NTR to transduce proNGF-induced signaling events required for TNFα production by Müller glial cells and that the TNFα kills RGCs through a p75NTR-independent mechanism.

Discussion

This study reports three major findings. First, proNGF leads to striking neuronal death in the adult rodent retina in vivo. Second, proNGF mediates RGC death indirectly via a non-cell-autonomous mechanism that involves TNFα production by Müller glia. Third, proNGF-induced death requires p75NTR, sortilin, and NRAGE, which cooperate to stimulate TNFα production by Müller cells.

p75NTR is an important neuronal signaling protein that interacts with numerous ligands and coreceptors to exert a wide range of functions. The role of p75NTR as an apoptotic receptor is well established as it has been shown to facilitate developmental cell death of peripheral sympathetic neurons and early retinal neurons (8, 24 26). p75NTR has also been implicated in cell loss following various forms of CNS injury and promotes apoptosis of cortical and hippocampal neurons, basal forebrain neurons, oligodendrocytes, and photoreceptor cells (8, 27 31). Overall, the functional role of p75NTR in neuronal death is best understood in neurons that endogenously express this receptor. In this study, however, we identify a unique mechanism by which p75NTR in glial cells can profoundly influence neuronal death by activating production of neurotoxic TNFα in the adult retina in vivo.

Recent studies have indicated that proNGF, but not NGF, functions as a potent proapoptotic ligand that binds to a cell surface complex of p75NTR and sortilin (5). Consistent with this, we showed that fully processed NGF does not share the apoptotic effect of proNGF and that proNGF is unable to induce retinal cell death in mice rendered null for sortilin. NRAGE is a crucial adaptor protein required for p75NTR-dependent apoptosis in cell lines, in primary cells, and in vivo (6). Consistent with this, we found that NRAGE is also necessary for proNGF-induced death of RGCs within the adult retina. Previous studies have established that RGCs express abundant p75NTR during retinal development (25) and that p75NTR and sortilin collaborate to induce NGF-dependent apoptosis of a subset of these neurons at embryonic day (E)15 (8, 25, 26). Therefore, it is possible that proNGF induces cell death in the adult retina by directly binding to a p75NTR–sortilin complex on adult RGCs. This is very unlikely, however, because examination of p75NTR expression in the adult rodent retina using light and electron microscopy has established that retinal p75NTR expression is confined to Müller glial cells (9, 12 15). A recent study reported that sortilin is expressed by Müller glia in the adult retina (16), and the data shown here indicate that NRAGE is also expressed in these glial cells. Therefore, association of proNGF with p75NTR and sortilin on Müller cells must induce death of RGCs through an indirect, non-cell-autonomous pathway.

Pharmacological or genetic blockade of TNFα dramatically reduced proNGF-induced RGC death, indicating that Müller cell-derived TNFα plays a crucial role in neuronal loss. There are several direct and indirect mechanisms by which TNFα produced by Müller cells could kill RGCs but two predominate. First, previous work established that TNFα can directly kill primary cortical neurons via a caspase 8-dependent mechanism in models of excitotoxicity (32, 33). It is thus possible that direct caspase activation occurs in RGCs. However, caspase-8 inhibitors that we validated in vivo and in vitro did not block proNGF-induced death of RGCs. Thus, we favor a second possibility, which involves the recent discovery that TNFα promotes the selective insertion of Ca2+-permeable AMPA receptors (AMPARs) into the neuronal cell surface (34, 35). Under physiological circumstances, TNFα-mediated increase in Ca2+-permeable AMPARs plays a role in synaptic scaling (36) but during injury, TNFα-mediated increase in these channels can facilitate death of primary hippocampal and spinal cord neurons (37, 38). Importantly, this mechanism of cell death may play a role in RGC loss after injury. For example, RGCs lacking TNFR1 are protected following optic nerve crush (39), and we recently showed that TNFα-mediated increase in cell surface Ca2+-permeable AMPARs leads to RGC loss in vivo (15).

Glaucoma is a group of diseases characterized by progressive optic nerve degeneration leading to visual field loss and irreversible blindness. A common characteristic of all forms of glaucoma is the death of RGCs (40). Of significant interest, TNFα and TNFR1 are up-regulated in human donor eyes with glaucoma (19, 41, 42), TNFα levels are increased in the aqueous humor of glaucoma patients (43), and TNFα gene polymorphisms have been correlated with primary open angle glaucoma (44, 45). Therefore, an important priority in future studies will be to determine if the proNGF, p75NTR, and TNFα cascade described here contributes to retinal degeneration and optic neuropathy in preclinical models of disease and in humans.

Several recent studies have highlighted the important role that non-cell-autonomous mechanisms play in neuronal cell death, notably in models of amyotrophic lateral sclerosis, spinocerebellar ataxia, and Huntington disease (46). TNFα is a hallmark of acute and chronic neuroinflammation and has emerged as an important candidate for mediating non-cell-autonomous effects in these conditions (47). p75NTR expressed by cholinergic neurons is required for production of an unknown factor that facilitates GABAergic neuron development (48), and p75NTR expressed on Müller glial cells mediates light-induced photoreceptor death via a non-cell-autonomous pathway (9). The potential role of TNFα downstream of these p75NTR-dependent events will be an interesting topic for future work.

In summary, our work demonstrates that proNGF can induce neuronal death in the retina through a non-cell-autonomous mechanism that involves the activation of p75NTR and production of TNFα by Müller glial cells. These findings raise the possibility that non-cell-autonomous events may be a general feature of p75NTR-dependent cell apoptosis in vivo.

Materials and Methods

Experimental Animals.

Procedures were carried out in adult C57BL/6 transgenic or wild-type littermate control mice, with the exception of results shown in Fig. 1A that were carried out in adult Sprague-Dawley rats. All animal procedures were performed in accordance with the policies on the Use of Animals in Neuroscience Research and the Canadian Council on Animal Care guidelines (49). p75NTR (50), TNFα (51), and NRAGE (6) null mice have been previously described. To inactivate the sortilin gene in ES cells we used the recombination cloning vector pML. A 4.6-kb fragment of the 5′-flanking genomic sequence and a 3.2-kb fragment of the 3′-flanking region of sortilin were subcloned upstream and downstream, respectively, of the neomycin resistance gene within the vector. The Neomycin/G418 in the pML vector was used for positive selection. This vector contains a thymidine kinase gene (TK) that in combination with gancyclovir was used for negative selection. The targeting construct was linearized by PmeI restriction digestion and electroporated into ES cells. These G418 and gancyclovir-resistant ES cell clones were screened by Southern blot after digestion of the ES genomic DNA with HindIII. The homologous recombination resulted in the replacement of a segment between exons 2 and intron 3 of the sortilin gene with the neomycin resistance cassette. Chimeric cells were injected into C57BL/6 blastocysts giving rise to chimeric mice, which were then backcrossed to C57BL/6 mice to identify if the germ-line transmission of the mutant allele had taken place (52). These heterozygotes were backcrossed with C57BL/6 mice for a minimum of seven generations before they were used in this study. All genotypes were verified by PCR using pfuTurbo (Stratagene). The number of animals used in each experiment (n) is shown in each corresponding graph.

Intraocular Injections.

A mutant form of proNGF that is resistant to cleavage by proteases (proNGFmut-m, 25 ng/μL, Alomone Labs) was injected into the vitreous chamber of the left eye using a 10-μL Hamilton syringe adapted with a 32-gauge glass microneedle (total volume: 2 μL). The average vitreous fluid volume in adult mice is estimated to be ~10 μL (53 55); therefore, the concentration of proNGF that reached RGCs was 0.1 μM. ProNGF was injected alone or in combination with Etanercept (Enbrel, 25 μg/μL, Wyeth), the p75NTR antibody REX (10 μg/μL), or an Fc control (25 μg/μL, Sigma). Control eyes were injected with mature NGF (0.1 μg/μL, human recombinant NGF, PeproTech), TNFα (200 ng/mL, murine recombinant TNFα, R&D Systems), or vehicle (PBS). Intraocular injections were performed under general anesthesia (2% Isoflurane/oxygen mixture, 0.8 L/min). The needle tip was inserted into the superior hemisphere of the eye, at a 45° angle through the sclera into the vitreous body. This route of administration avoided retinal detachment or injury to eye structures, including the iris and lens, which release factors that induce neuronal survival (56, 57).

Retrograde Labeling and Quantification of Neuronal Survival.

Retrograde labeling of RGCs was performed using Fluorogold (2%, Fluorochrome) in 0.9% NaCl, which was applied to the superior colliculus as described (58). Subsequent surgical procedures were performed at 1 week after Fluorogold application (59 62). Mice were perfused with 4% paraformaldehyde; eyes were dissected and flat mounted vitreal side up on glass sides. Fluorogold-positive RGCs were counted in 12 retinal zones: Three areas in each eye quadrant (dorsal, ventral, nasal, and temporal) located at 0.5, 1.0, and 1.5 mm from the optic nerve head were examined (58), corresponding to a total area of 0.5 mm2. Statistical analyses were performed using one-way analysis of variance (ANOVA) followed by a nonparametric test (Bonferroni’s multiple-comparison test) or by a Student’s t test, as indicated in the figure legends.

Retinal Immunohistochemistry.

Mice were perfused with 4% paraformaldehyde and retinal sections were prepared as above. Tissue sections were incubated in 3% BSA and 0.3% Triton X-100 (Sigma) to block nonspecific binding and then incubated with primary antibodies (see list below) overnight at 4 °C, followed by incubation with secondary antibodies at room temperature. Slides were mounted with SlowFade (Molecular Probes) and visualized on a Zeiss Axioskop 2 Plus microscope (Carl Zeiss Canada) or a confocal microscope (Leica Microsystems). Primary antibodies used were anti-cellular retinaldehyde-binding protein (1:1,000, gift from J. C. Saari, University of Washington, Seattle, WA), anti-p75NTR (REX, 2 ng/μL) (63), anti-NRAGE (5 ng/μL, Orbigen), and anti-TNFα (0.4 μg/mL, Chemicon). The secondary antibodies used were sheep anti-mouse IgG (1 μg/mL, FITC conjugate, Sigma) or anti-rabbit IgG (1 μg/mL, Cy3, Jackson ImmunoResearch Laboratories).

Immunoblot Analysis.

Retinas were homogenized in lysis buffer [20 mM Tris (pH 8.0), 135 mM NaCl, 1% SDS, and 10% glycerol supplemented with protease inhibitors] and centrifuged at 14,000 rpm for 5 min. The supernatants were collected, diluted in Laemmli sample buffer (4% SDS, 10% glycerol, 0.004% bromophenol blue, 0.1 M DTT, and 0.125 M Tris, pH 6.8), and analyzed by SDS–polyacrylamide gel electrophoresis and immunoblotting following standard protocols. Primary antibodies were against p75NTR (REX, 1:1,000) (64), NRAGE (1:1,000) (64), Sortilin (1:1,000) (BD Biosciences), TNFα (0.2 μg/mL, Santa Cruz Biotechnology), and β-actin (1:30,000) (Sigma). Secondary HRP-coupled antibodies were obtained from Jackson ImmunoResearch Laboratories. Protein signals were detected using a chemiluminescence reagent (ECL, Amersham Biosciences) followed by exposure of blots to X-Omat (Kodak) imaging film.

Supplementary Material

Supporting Information:

Acknowledgments

This work was supported by independent grants from the Canadian Institutes of Health Research (to A.D.P. and P.A.B.). F.L.-J. is recipient of a Fonds de Recherche en Santé du Québec doctoral fellowship, A.D.P. holds a Fonds de Recherche en Santé du Québec Chercheur Senior Scholarship, and P.A.B. holds a Fonds de Recherche en Santé du Québec Chercheur National and is a McGill Dawson Scholar.

Footnotes

The authors declare no conflict of interest.

This article is a PNAS Direct Submission. M.V.C. is a guest editor invited by the Editorial Board.

This article contains supporting information online at www.pnas.org/cgi/content/full/0909276107/DCSupplemental.

References

1. Bruno MA, Cuello AC. Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor, and its degradation by a protease cascade. Proc Natl Acad Sci USA. 2006;103:6735–6740. [PMC free article] [PubMed]
2. Fahnestock M, Michalski B, Xu B, Coughlin MD. The precursor pro-nerve growth factor is the predominant form of nerve growth factor in brain and is increased in Alzheimer’s disease. Mol Cell Neurosci. 2001;18:210–220. [PubMed]
3. Lee R, Kermani P, Teng KK, Hempstead BL. Regulation of cell survival by secreted proneurotrophins. Science. 2001;294:1945–1948. [PubMed]
4. Hempstead BL. Dissecting the diverse actions of pro- and mature neurotrophins. Curr Alzheimer Res. 2006;3:19–24. [PubMed]
5. Nykjaer A, et al. Sortilin is essential for proNGF-induced neuronal cell death. Nature. 2004;427:843–848. [PubMed]
6. Bertrand MJ, et al. NRAGE, a p75NTR adaptor protein, is required for developmental apoptosis in vivo. Cell Death Differ. 2008;15:1921–1929. [PMC free article] [PubMed]
7. Linggi MS, et al. Neurotrophin receptor interacting factor (NRIF) is an essential mediator of apoptotic signaling by the p75 neurotrophin receptor. J Biol Chem. 2005;280:13801–13808. [PubMed]
8. Frade JM, Barde YA. Genetic evidence for cell death mediated by nerve growth factor and the neurotrophin receptor p75 in the developing mouse retina and spinal cord. Development. 1999;126:683–690. [PubMed]
9. Harada T, et al. Modification of glial-neuronal cell interactions prevents photoreceptor apoptosis during light-induced retinal degeneration. Neuron. 2000;26:533–541. [PubMed]
10. Srinivasan B, Roque CH, Hempstead BL, Al-Ubaidi MR, Roque RS. Microglia-derived pronerve growth factor promotes photoreceptor cell death via p75 neurotrophin receptor. J Biol Chem. 2004;279:41839–41845. [PubMed]
11. Weskamp G, Reichardt LF. Evidence that biological activity of NGF is mediated through a novel subclass of high affinity receptors. Neuron. 1991;6:649–663. [PubMed]
12. Ding J, Hu B, Tang LS, Yip HK. Study of the role of the low-affinity neurotrophin receptor p75 in naturally occurring cell death during development of the rat retina. Dev Neurosci. 2001;23:390–398. [PubMed]
13. Hu B, Yip HK, So K-F. Localization of p75 neurotrophin receptor in the retina of the adult SD rat: an immunocytochemical study at light and electron microscopic levels. Glia. 1998;24:187–197. [PubMed]
14. Hu B, Yip HK, So KF. Expression of p75 neurotrophin receptor in the injured and regenerating rat retina. Neuroreport. 1999;10:1293–1297. [PubMed]
15. Lebrun-Julien F, et al. Excitotoxic death of retinal neurons in vivo occurs via a non-cell-autonomous mechanism. J Neurosci. 2009;29:5536–5545. [PubMed]
16. Xu F, et al. Immunohistochemical localization of sortilin and p75(NTR) in normal and ischemic rat retina. Neurosci Lett. 2009;454:81–85. [PubMed]
17. Berger S, et al. Deleterious role of TNF-alpha in retinal ischemia-reperfusion injury. Invest Ophthalmol Vis Sci. 2008;49:3605–3610. [PubMed]
18. Nakazawa T, et al. Tumor necrosis factor-alpha mediates oligodendrocyte death and delayed retinal ganglion cell loss in a mouse model of glaucoma. J Neurosci. 2006;26:12633–12641. [PubMed]
19. Tezel G, Li LY, Patil RV, Wax MB. TNF-alpha and TNF-alpha receptor-1 in the retina of normal and glaucomatous eyes. Invest Ophthalmol Vis Sci. 2001;42:1787–1794. [PubMed]
20. Hiscott J, et al. Characterization of a functional NF-kappa B site in the human interleukin 1 beta promoter: Evidence for a positive autoregulatory loop. Mol Cell Biol. 1993;13:6231–6240. [PMC free article] [PubMed]
21. Mori N, Prager D. Transactivation of the interleukin-1alpha promoter by human T-cell leukemia virus type I and type II Tax proteins. Blood. 1996;87:3410–3417. [PubMed]
22. Shakhov AN, Collart MA, Vassalli P, Nedospasov SA, Jongeneel CV. Kappa B-type enhancers are involved in lipopolysaccharide-mediated transcriptional activation of the tumor necrosis factor alpha gene in primary macrophages. J Exp Med. 1990;171:35–47. [PMC free article] [PubMed]
23. Fantuzzi F, Del Giglio M, Gisondi P, Girolomoni G. Targeting tumor necrosis factor alpha in psoriasis and psoriatic arthritis. Expert Opin Ther Targets. 2008;12:1085–1096. [PubMed]
24. Majdan M, et al. Transgenic mice expressing the intracellular domain of the p75 neurotrophin receptor undergo neuronal apoptosis. J Neurosci. 1997;17:6988–6998. [PubMed]
25. Harada C, et al. Effect of p75NTR on the regulation of naturally occurring cell death and retinal ganglion cell number in the mouse eye. Dev Biol. 2006;290:57–65. [PubMed]
26. Jansen P, et al. Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury. Nat Neurosci. 2007;10:1449–1457. [PubMed]
27. Beattie MS, et al. ProNGF induces p75-mediated death of oligodendrocytes following spinal cord injury. Neuron. 2002;36:375–386. [PMC free article] [PubMed]
28. Friedman WJ. Neurotrophins induce death of hippocampal neurons via the p75 receptor. J Neurosci. 2000;20:6340–6346. [PubMed]
29. Harrington AW, et al. Secreted proNGF is a pathophysiological death-inducing ligand after adult CNS injury. Proc Natl Acad Sci USA. 2004;101:6226–6230. [PMC free article] [PubMed]
30. Roux PP, Colicos MA, Barker PA, Kennedy TE. p75 neurotrophin receptor expression is induced in apoptotic neurons after seizure. J Neurosci. 1999;19:6887–6896. [PubMed]
31. Volosin M, et al. Interaction of survival and death signaling in basal forebrain neurons: Roles of neurotrophins and proneurotrophins. J Neurosci. 2006;26:7756–7766. [PubMed]
32. Kaushal V, Schlichter LC. Mechanisms of microglia-mediated neurotoxicity in a new model of the stroke penumbra. J Neurosci. 2008;28:2221–2230. [PubMed]
33. Velier JJ, et al. Caspase-8 and caspase-3 are expressed by different populations of cortical neurons undergoing delayed cell death after focal stroke in the rat. J Neurosci. 1999;19:5932–5941. [PubMed]
34. Ogoshi F, et al. Tumor necrosis-factor-alpha (TNF-alpha) induces rapid insertion of Ca2+-permeable alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)/kainate (Ca-A/K) channels in a subset of hippocampal pyramidal neurons. Exp Neurol. 2005;193:384–393. [PubMed]
35. Stellwagen D, Beattie EC, Seo JY, Malenka RC. Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. J Neurosci. 2005;25:3219–3228. [PubMed]
36. Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-alpha. Nature. 2006;440:1054–1059. [PubMed]
37. Ferguson AR, et al. Cell death after spinal cord injury is exacerbated by rapid TNF alpha-induced trafficking of GluR2-lacking AMPARs to the plasma membrane. J Neurosci. 2008;28:11391–11400. [PMC free article] [PubMed]
38. Leonoudakis D, Zhao P, Beattie EC. Rapid tumor necrosis factor alpha-induced exocytosis of glutamate receptor 2-lacking AMPA receptors to extrasynaptic plasma membrane potentiates excitotoxicity. J Neurosci. 2008;28:2119–2130. [PubMed]
39. Tezel G, Yang X, Yang J, Wax MB. Role of tumor necrosis factor receptor-1 in the death of retinal ganglion cells following optic nerve crush injury in mice. Brain Res. 2004;996:202–212. [PubMed]
40. Quigley HA. Glaucoma: Macrocosm to microcosm the Friedenwald lecture. Invest Ophthalmol Vis Sci. 2005;46:2662–2670. [PubMed]
41. Yan X, Tezel G, Wax MB, Edward DP. Matrix metalloproteinases and tumor necrosis factor alpha in glaucomatous optic nerve head. Arch Ophthalmol. 2000;118:666–673. [PubMed]
42. Yuan L, Neufeld AH. Tumor necrosis factor-alpha: A potentially neurodestructive cytokine produced by glia in the human glaucomatous optic nerve head. Glia. 2000;32:42–50. [PubMed]
43. Sawada H, Fukuchi T, Tanaka T, Abe H. Tumor necrosis factor-{alpha} concentrations in the aqueous humor of glaucoma patients. Invest Ophthalmol Vis Sci. 2010 10.1167/iovs.09-4247. [PubMed]
44. Funayama T, et al. Variants in optineurin gene and their association with tumor necrosis factor-alpha polymorphisms in Japanese patients with glaucoma. Invest Ophthalmol Vis Sci. 2004;45:4359–4367. [PubMed]
45. Lin HJ, et al. Association of tumour necrosis factor alpha -308 gene polymorphism with primary open-angle glaucoma in Chinese. Eye (Lond) 2003;17:31–34. [PubMed]
46. Lobsiger CS, Cleveland DW. Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease. Nat Neurosci. 2007;10:1355–1360. [PMC free article] [PubMed]
47. McCoy MK, Tansey MG. TNF signaling inhibition in the CNS: Implications for normal brain function and neurodegenerative disease. J Neuroinflammation. 2008;5:45. [PMC free article] [PubMed]
48. Lin PY, Hinterneder JM, Rollor SR, Birren SJ. Non-cell-autonomous regulation of GABAergic neuron development by neurotrophins and the p75 receptor. J Neurosci. 2007;27:12787–12796. [PubMed]
49. Olfert ED, Cross BM, McWilliams AA. The Guide to the Care and Use of Experimental Animals. Ottawa, ON, Canada: Canadian Council on Animal Care; 1993.
50. Lee K-F, et al. Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system. Cell. 1992;69:737–749. [PubMed]
51. Taniguchi T, Takata M, Ikeda A, Momotani E, Sekikawa K. Failure of germinal center formation and impairment of response to endotoxin in tumor necrosis factor alpha-deficient mice. Lab Invest. 1997;77:647–658. [PubMed]
52. Zeng J, Racicott J, Morales CR. The inactivation of the sortilin gene leads to a partial disruption of prosaposin trafficking to the lysosomes. Exp Cell Res. 2009;315:3112–3124. [PubMed]
53. Remtulla S, Hallett PE. A schematic eye for the mouse, and comparisons with the rat. Vision Res. 1985;25:21–31. [PubMed]
54. Sharma S, Ball SL, Peachey NS. Pharmacological studies of the mouse cone electroretinogram. Vis Neurosci. 2005;22:631–636. [PubMed]
55. Yu D-Y, Cringle SJ. Oxygen distribution in the mouse retina. Invest Ophthalmol Vis Sci. 2006;47:1109–1112. [PubMed]
56. Fischer D, Heiduschka P, Thanos S. Lens-injury-stimulated axonal regeneration throughout the optic pathway of adult rats. Exp Neurol. 2001;172:257–272. [PubMed]
57. Leon S, Yin Y, Nguyen J, Irwin N, Benowitz LI. Lens injury stimulates axon regeneration in the mature rat optic nerve. J Neurosci. 2000;20:4615–4626. [PubMed]
58. Sapieha PS, et al. Receptor protein tyrosine phosphatase sigma inhibits axon regrowth in the adult injured CNS. Mol Cell Neurosci. 2005;28:625–635. [PubMed]
59. Berkelaar M, Clarke DB, Wang Y-C, Bray GM, Aguayo AJ. Axotomy results in delayed death and apoptosis of retinal ganglion cells in adult rats. J Neurosci. 1994;14:4368–4374. [PubMed]
60. Cheng L, Sapieha P, Kittlerová P, Hauswirth WW, Di Polo A. TrkB gene transfer protects retinal ganglion cells from axotomy-induced death in vivo. J Neurosci. 2002;22:3977–3986. [PubMed]
61. Mansour-Robaey S, Clarke DB, Wang Y-C, Bray GM, Aguayo AJ. Effects of ocular injury and administration of brain-derived neurotrophic factor on survival and regrowth of axotomized retinal ganglion cells. Proc Natl Acad Sci USA. 1994;91:1632–1636. [PMC free article] [PubMed]
62. Peinado-Ramón P, Salvador M, Villegas-Pérez MP, Vidal-Sanz M. Effects of axotomy and intraocular administration of NT-4, NT-3, and brain-derived neurotrophic factor on the survival of adult rat retinal ganglion cells. A quantitative in vivo study. Invest Ophthalmol Vis Sci. 1996;37:489–500. [PubMed]
63. Bhakar AL, et al. The p75 neurotrophin receptor (p75NTR) alters tumor necrosis factor-mediated NF-kappaB activity under physiological conditions, but direct p75NTR-mediated NF-kappaB activation requires cell stress. J Biol Chem. 1999;274:21443–21449. [PubMed]
64. Salehi AH, et al. NRAGE, a novel MAGE protein, interacts with the p75 neurotrophin receptor and facilitates nerve growth factor-dependent apoptosis. Neuron. 2000;2:279–288. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...