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Address correspondence to Bruce D. Carter, Department of Biochemistry, 655 Light Hall, Vanderbilt University School of Medicine, Nashville, TN 37232. Tel.: (615) 936-3041. Fax: (615) 343-0704. E-mail: bruce.carter{at}mcmail.vanderbilt.edu
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Abstract |
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Key Words: neurotrophin; apoptosis; Jun; Trk; nerve growth factor
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Introduction |
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One of the neuronal populations best characterized for its dependence on neurotrophins is the superior cervical ganglia (SCG). This group of sympathetic neurons expresses the TrkA and p75 receptors, and is dependent on NGF for survival and differentiation during development. Some of the developmental apoptosis of sympathetic neurons has also been suggested to be the result of BDNF binding to p75 (Bamji et al., 1998). These apoptotic responses can also be recapitulated in cultured SCG neurons by NGF withdrawal (Martin et al., 1988) or by the addition of BDNF to neurons maintained in depolarizing levels of potassium (Bamji et al., 1998).
The molecular mechanisms by which NGF removal induces apoptosis have been shown to involve cytochrome c translocation from the mitochondria to the cytosol, which is dependent on the proapoptotic BCL-2 family members, BAX (Deckwerth et al., 1996; Lentz et al., 1999) and BIM (Putcha et al., 2001; Whitfield et al., 2001). After cytochrome c release, a cascade of caspase activation occurs, resulting in the classical characteristics of apoptosis. However, microinjection of cytochrome c into neurons is not sufficient to induce cell death, thus NGF withdrawal activates additional pathways that induce a condition referred to as "competence to die" (Deshmukh and Johnson, 1998). This "competence" likely involves the up-regulation of proapoptotic genes because apoptosis induced by NGF withdrawal is transcription and translation dependent (Martin et al., 1988). The increase in transcription has been attributed to the stabilization of the tumor suppressor p53 (Aloyz et al., 1998; Pozniak et al., 2000) and activation of c-Jun, a component of the AP-1 transcription factor (Estus et al., 1994; Ham et al., 1995). Analysis of the c-jun-/- mice has not been possible due to early embryonic lethality (Hilberg et al., 1993; Johnson et al., 1993); however, an increase in both c-Jun mRNA (Estus et al., 1994) and the activated, phosphorylated form of the protein (Ham et al., 1995) have been observed after NGF withdrawal. In addition, microinjection of antibodies to c-Jun (Estus et al., 1994), or introduction of a cDNA encoding a mutant c-Jun, into SCG neurons (Ham et al., 1995; Whitfield et al., 2001) was demonstrated to protect them from death after NGF removal. However, these experiments should be interpreted with caution because there may be excessively high levels of ectopic protein and the mutant c-Jun may still dimerize with wild-type (wt) AP-1 members and alter transcription of multiple AP-1-responsive genes.
The mechanism by which activation of the p75 receptor induces apoptosis is much less understood. Similar to NGF withdrawal, neurotrophin binding selectively to p75 has been shown to increase phosphorylation of c-Jun (Bamji et al., 1998) and to activate the upstream kinase, c-Jun NH2-terminal kinase (JNK; Casaccia-Bonnefil et al., 1996). Furthermore, blocking the activation of JNK with a pharmacological inhibitor (Yoon et al., 1998) or a dominant-negative JNK (Harrington et al., 2002), prevented p75-mediated apoptosis of oligodendrocytes. However, the requirement for c-Jun in p75 signaling cell death has not been investigated, nor has it been determined whether this is a transcription-dependent process.
To address the role of c-jun in the apoptosis of SCG neurons, we generated a conditional c-junnull allele by flanking it with loxP sites, and used adenovirally delivered Cre recombinase to delete the gene in SCG neurons. Our findings demonstrate that c-Jun is essential for neuronal cell death after NGF deprivation, but not by neurotrophin binding to p75. Nevertheless, p75-mediated apoptosis was dependent on macromolecular synthesis because it was blocked by cycloheximide. Therefore, we propose that there are divergent, transcriptionally dependent pathways initiated by these two inducers of apoptosis.
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Results |
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c-jun is not necessary for sympathetic neuron death in response to p75 activation
Neurotrophin binding selectively to the p75 receptor can activate an apoptotic program in a variety of neural cells (Barrett, 2000). In sympathetic neurons, which express only the neurotrophin receptors p75 and TrkA, p75 can be selectively activated by BDNF, and this was reported to lead to cell death (Bamji et al., 1998). To culture these neurons in the absence of NGF, the neurons were kept in mildly depolarizing media containing 12.5 mM KCl. Similar to previous findings, we observed an 87% increase in the number of apoptotic nuclei in cultured SCG neurons after a 48-h treatment with BDNF (Figs. 46). Moreover, this effect could be inhibited with an antibody to the extracellular domain of p75, confirming the involvement of this receptor (Fig. 4).
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To determine whether protein synthesis is required for cell death activated by p75, SCGs isolated from wt mice were incubated with cycloheximide at a concentration of 1 µg/ml at the time of NGF removal and BDNF treatment. 48 h thereafter, apoptosis was assessed by nuclear morphology after DAPI staining. In the presence of this protein translation inhibitor, BDNF-induced cell death was completely abrogated (Fig. 6). These results suggest that, like trophic factor withdrawal, apoptosis induced by p75 activation is also a transcription-dependent process.
Because c-Jun was required for the neurons to activate their cell death program after NGF removal, we wanted to determine whether this transcription factor is also an essential component for p75-induced cell death. Therefore, neurons isolated from c-junfl/fl mice were uninfected or infected with the adenovirus expressing Cre recombinase or GFP, then maintained for 48 h in medium containing 12.5 mM KCl, with or without 100 ng/ml BDNF. The neurons were fixed and stained with an antibody against Cre recombinase to detect Cre-immunopositive neurons, and with DAPI to detect apoptotic profiles. Surprisingly, the addition of BDNF to the medium induced an equivalent amount of death in neurons that were uninfected (50.2 ± 4.9%), infected with adeno-GFP (50.5 ± 2.1%), and those expressing Cre recombinase (57.1 ± 2.7%; Fig. 7), indicating that c-Jun is not an essential component in sympathetic neuronal death induced by p75 activation.
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Discussion |
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Sympathetic neurons have been well characterized as an in vitro model for neuronal apoptosis induced by trophic factor deprivation. Removal of NGF from the cultures activates a cell death program that is dependent on transcription and translation (Martin et al., 1988). One of the first genes shown to be induced after NGF withdrawal was the protooncogene c-jun (Estus et al., 1994). This transcription factor is an immediate early gene that up-regulates its own mRNA. It functions to drive gene expression by homo- or heterodimerizing with other members of the AP-1 family, including c-fos, Fos B, Fra 1 and 2, ATF-2, c-jun, Jun B, and Jun D. Various combinations of the AP-1 family members lead to different DNA binding specificities. Transactivation of c-jun is a two-step process requiring docking of JNK to an NH2-terminal sequence referred to as the -domain, followed by phosphorylation on serines 63 and 73. The ability to activate transcription depends on both the phosphorylation state of c-Jun and its dimeric partner (for review see Mechta-Grigoriou et al., 2001). Some members of the family can even antagonize transcription by potent activators such as homodimers of c-Jun (Deng and Karin, 1993) or heterodimers of c-Fos (Wisdom and Verma, 1993). Curiously, the transforming mutation of this protooncogene is a deletion of the
-domain, although how this deletion results in unregulated growth is not clear. Hence, this immediate early gene is regulated in a complex, incompletely understood manner.
A variety of growth factors can activate the AP-1 complex and promote progression through the cell cycle, in part, through activation of cyclin D1 (Wisdom et al., 1999). In addition, many cytokines and inducers of cellular stress such as UV and -radiation, osmotic shock, hypoxia, and withdrawal of trophic support activate JNK, and subsequently, c-Jun. Paradoxically, this activation has been suggested to promote survival in dividing cells, such as fibroblasts, yet lead to apoptosis in post-mitotic neurons (for review see Shaulian and Karin, 2001). Inhibition of JNK activation in sympathetic neurons was shown to provide protection from NGF withdrawal (Maroney et al., 1999). Similarly, microinjection of antibodies to c-Jun (Estus et al., 1994), cDNA encoding c-Jun mutants (Ham et al., 1995), or expression of c-Jun mutants using adenovirus (Whitfield et al., 2001) attenuated apoptosis in these neurons after trophic factor deprivation, whereas overexpression of c-Jun lead to cell death (Ham et al., 1995). However, a high level expression of ectopic protein may interfere with the normal function of the neuron. For example, overexpression of mutant c-Jun could alter c-Fos dimers, which have also been implicated in regulating survival (Smeyne et al., 1993; Preston et al., 1996). Moreover, dominant-negative mutants lacking the
-domain may well maintain the activity that leads to transformation in fibroblasts. Therefore, we chose to use a genetic approach to address the role of c-Jun in these neurons. Unfortunately, the deletion of c-jun is embryonic lethal at E14, before the sympathetic neurons undergo naturally occurring cell death (Wright et al., 1983). Therefore, we used a Cre-lox system to excise this gene. Our findings demonstrate a requirement for c-Jun in apoptosis induced by NGF removal, in agreement with previous studies.
Although neuronal apoptosis induced by trophic factor withdrawal is dependent on transcription and c-Jun, it is not clear what the relevant target genes are for this AP-1 factor. The activation of JNK in neurons has been suggested to lead to the up-regulation of two members of the proapoptotic Bcl-2 family, BAX (Miller et al., 1997) and BIM (Putcha et al., 2001; Whitfield et al., 2001). However, it is likely that c-Jun also interacts with other transcriptional elements to affect the expression of apoptotic genes. For example, the upstream kinase, JNK, has also been shown to phosphorylate p53 (Fuchs et al., 1998), which can up-regulate BAX (Miyashita and Reed, 1995). Indeed, reduced apoptosis in sympathetic ganglia was observed in p53+/- mice, and expression of the viral p53 inhibitor (E1B55K) protected these neurons in culture after NGF removal (Aloyz et al., 1998). Thus, the interplay between p53 and c-Jun in regulating neuronal survival and death genes remains to be determined. It is interesting to note that a recent study demonstrated an intimate relationship between c-Jun and p53 after UV irradiation (Shaulian et al., 2000). The induction of c-Jun after a UV response resulted in antagonism of p53 at the p21 promoter. This caused the DNA-damaged fibroblasts to reenter the cell cycle, triggering apoptosis. A similar mechanism may explain the dual dependence of neuronal apoptosis on c-Jun and p53. Both of these transcription factors may be required for the correct temporal regulation of genes key to neuronal apoptosis.
Sympathetic neurons express exclusively the neurotrophin receptors TrkA and p75, and therefore undergo apoptosis if they fail to innervate a target producing NGF (for review see Huang and Reichardt, 2001). In contrast, if these neurons come in contact with tissue producing a neurotrophin other than NGF, then p75 will be activated and apoptosis will result. Miller and colleagues have demonstrated such an effect in vivo, where mice with the BDNF gene deleted exhibit an increase in sympathetic neuron survival (Bamji et al., 1998). These authors suggest that although insufficient TrkA activation promotes cell death, neurotrophin binding selectively to p75 will result in a more rapid and efficient elimination of inappropriate connections.
There is accumulating evidence that activation of the p75 receptor induces apoptosis in a variety of neuronal (Rabizadeh et al., 1993; Barrett and Bartlett, 1994, Barrett and Georgiou, 1996; Friedman, 2000) and glial contexts (Casaccia-Bonnefil et al., 1996; Soilu-Hanninen et al., 1999), both during development (Frade et al., 1996, Frade and Barde, 1999) and after insult, such as nerve injury (Syroid et al., 2000; Harrington et al., 2002) or seizure (Roux et al., 1999). The molecular mechanisms mediating this effect, although largely undetermined, have been suggested to involve the transcription factor NF-B and the c-Jun kinase, JNK, both of which can be activated after neurotrophin binding to p75 (for review see Barrett, 2000). Paradoxically, in a manner reminiscent of TNF receptor signaling, p75 activation of NF-
B has been shown to promote survival (Hamanoue et al., 1999; Foehr et al., 2000; Gentry et al., 2000), whereas JNK has been implicated in the apoptotic response (Casaccia-Bonnefil et al., 1996; Yoon et al., 1998). In the presence of TrkA, NGF binding to p75 will only activate the pro-survival factor NF-
B while JNK activity is inhibited (Yoon et al., 1998). Hence, when the neuron contacts the appropriate target, binding of NGF to both TrkA and p75 coordinately promotes survival. In contrast, selective activation of p75 promotes apoptosis through JNK because attenuation of this kinase activity prevented the receptor-mediated cell death (Yoon et al., 1998; Harrington et al., 2002). Thus, whether induced by p75 activation or NGF withdrawal, programmed cell death in sympathetic neurons depends on the c-Jun activating kinase, JNK. Surprisingly, however, our findings demonstrate these death signals subsequently diverge. The deletion of c-Jun protected sympathetic neurons from apoptosis caused by trophic factor withdrawal; however, the ability of p75 to kill the cells was not altered. The apoptotic signal generated from p75 was inhibited by cycloheximide, suggesting a requirement for protein translation. Miller and colleagues demonstrated that the p53 inhibitor (E1B55K) can block sympathetic neuron death caused by BDNF (Aloyz et al., 1998). Hence, it is likely that the p75 apoptotic signal is through JNK activation of p53, resulting in the up-regulation of BAX and induction of apoptosis. However, it is notable that several p75-interacting proteins have been proposed to act in the nucleus (Casademunt et al., 1999; Chittka and Chao, 1999). Whether these interactors are affected by JNK remains to be determined.
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Materials and methods |
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The insertion of the neo gene into the 5' UTR of c-jun disrupts the expression of the gene, and therefore must be removed to allow tissue-specific activation. Hence, the targeted ES cells were transiently transfected with pCMV-Cre, and individual clones were isolated and screened by PCR to identify those with specific excision of the neo cassette. This analysis also identified some clones in which excision between the most upstream and downstream loxP sites occurred, verifying the ability of all three loxP sites to support Cre-mediated deletion. The removal of the neo gene was confirmed by Southern blotting, demonstrating that the targeted c-jun allele contains the protein coding sequence flanked by loxP sites (Fig. 1 D). The ES cells containing the floxed c-jun were then injected into blastocysts, and chimeric mice were obtained and mated. Germline transmission was confirmed by PCR using primers that flank the upstream loxP site (5'-GGAGAGTCCCTTCTCCCGCC-3' and 5'-GCTAGCACTCACGTTGGTAGG-3'; Fig. 1 E). The mice were crossed with the c-jun+/- to eventually obtain animals homozygous for the floxed allele in place of the wt gene, thus confirming that the loxP sites introduced do not interfere with normal c-Jun function.
Neuronal cultures
SCG from wt or postnatal day 1 c-jun fl/fl pups were isolated, and the sympathetic neurons dissociated by trituration after digestion with 0.25% trypsin and 0.3% collagenase for 15 min at 37°C. The nonneuronal cells were removed by a 2-h preplating on uncoated, FalconTM 60-mm plates (Becton Dickinson). The neurons were cultured on poly-L-ornithine and laminin-coated 4-well slides (Nalge Nunc International) at a density of 3,0004,000 cells/well in F-14+ media (Ham's F-14 containing 5% FCS, 2 mM L-glutamine, 60 ng/ml progesterone, 16 µg/ml putrescine, 400 ng/ml L-thyroxine, 38 ng/ml sodium selenite, 340 ng/ml tri-iodothyroxine, 5 µg/ml insulin, 100 U/ml penicillin, 100 µg/ml streptomycin, and 10 µM fluorodeoxyuridine; Imperial Labs) and 20 ng/ml NGF (Regeneron Pharmaceuticals, Inc.). The neurons were maintained for 35 d in the presence of NGF before being used for survival assays in NGF withdrawal and in p75 activation experiments.
Survival assays
For NGF withdrawal experiments, NGF was removed by washing the cultures twice with F-14+ media lacking NGF, and once with F-14+ containing anti-NGF antibody at 1 µg/ml (Sigma-Aldrich). For the p75 activation experiments, the procedure was similar, but after the washes with media lacking NGF, neurons were switched to media containing anti-NGF antibody together with 12.5 mM KCl, to promote survival, with or without 100 ng/ml BDNF (a gift from Regeneron Pharmaceuticals, Inc.). In experiments involving the inhibition of protein synthesis, SCGs were incubated with 1 µg/ml cycloheximide (Sigma-Aldrich) at the time of NGF removal or BDNF treatment. This concentration of cycloheximide inhibited 7080% of protein synthesis based on [35S]methionine labeling of the neurons as in Martin et al. (1988) (data not shown). Some neurons were also treated at the time of NGF withdrawal with an antiserum raised to the extracellular domain of p75 (diluted 1:500; a gift of M.V. Chao, Skirball Institute, New York University, New York, NY).
2 d after the switch to NGF-free or BDNF-containing media, or after the indicated time, the cells were fixed in 4% PFA and the number of apoptotic neurons, identified by DAPI staining, was counted in five random fields (at least 50 neurons counted/well). In the assays done with infected neurons, only Cre-immunopositive or GFP-expressing cells were considered.
Viral infections
Two different recombinant adenoviruses were used, one expressing Cre recombinase and the other expressing GFP, as a control for adenoviral infection. The GFP-adenovirus was provided by S.O. Yoon (Ohio State University, Columbus, OH) (Harrington et al., 2002) and the Cre-adenovirus was as used previously (Seagroves et al., 2001). The adenoviruses were amplified in 293 cells, the viral solution was purified on CsCl2 gradients, and viral infectivity was determined on 3T3 cells and neurons. The neurons were cultured for 35 d in 20 ng/ml NGF, infected with 1.6 x 109 particles/ml of recombinant adenovirus for 2 h in serum-free F-14+ media, and thereafter serum-containing F-14+ media was added. This concentration of virus was chosen in order to obtain 95% or better infection. Although there was a low level of toxicity due to the viral infection (Fig. 3 D), using 10-fold less virus did not alter the amount of cell death among infected neurons, yet the percentage of infected cells decreased to 70%. 1 d after infection (1824 h), the virus was removed and cells were fed with fresh NGF-free or BDNF-containing F-14+ media for survival assays under conditions of NGF withdrawal or p75 activation, respectively.
Genomic PCR to detect c-jun
To confirm the deletion of c-jun, the genomic DNA was isolated from sympathetic neurons that were uninfected, or 48 h after infection with the adenovirus expressing GFP or Cre. The c-jun locus was amplified by PCR using primers flanking the loxP site (5'-AGCAACTTTCCTGACCCAGA-3') and (5'-CGTCCCTGCTTCTGTAACAA-3') with the following PCR conditions of: 1 cycle of 94°C for 2 min, 52°C for 30 s, and 72°C for 30 s, and then 30 cycles at 94°C for 30 s, 52°C for 30 s, and 72°C for 30 s). As a control to demonstrate the presence of genomic DNA, the NF-B subunit p65 was amplified using primers 5'-CCTGGGGATCCAGTGTGTGAAGAAGCG-3'and 5'-AATCGGATGTGAGAGGACGACAGC-3' (PCR conditions of the following: 94°C for 5 min, and then 40 cycles of 94°C for 1 min, 65°C for 1.5 min, and 72°C for 1 min).
Immunohistochemistry
Neurons grown as described under Neuronal cultures were rinsed in PBS, fixed in 4% PFA, and blocked with 10% goat serum in PT (PBS + 0.1% Triton X-100) followed by avidin-biotin block (Vectastain; Vector Laboratories). To detect Cre recombinase, cells were probed overnight at 4°C with a biotinylated antiserum to Cre recombinase (Covance, Inc.) diluted 1:100 in PT, followed by 20-min incubation with Cy2- or Cy3-streptavidin. To visualize c-Jun, cells were permeabilized for 2 min at 4°C in PT with 0.1% sodium citrate, blocked as for anti-Cre, and incubated with antic-Jun, diluted 1:500 (Cell Signaling Technology Inc.), for 1 h at RT followed by biotinylated antirabbit antibody and Cy3-streptavidin. Nuclei were stained with DAPI. The slides were then viewed by fluorescence microscopy (Carl Zeiss MicroImaging, Inc.).
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Acknowledgments |
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This work was supported by a National Institutes of Health grant (NS38220) to B.D. Carter and a Juvenile Diabetes Foundation grant (3-1999-229) to S. Kanwal.
Submitted: 26 December 2001
Revised: 10 May 2002
Accepted: 3 June 2002
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