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First published online 21 March 2007
doi: 10.1242/dev.02838
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Department of Molecular Biology of the Cell I, German Cancer Research Center, D-69120 Heidelberg, Germany.
Author for correspondence (e-mail:
g.schuetz{at}dkfz-heidelberg.de)
Accepted 16 February 2007
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SUMMARY |
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 TOP SUMMARY INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key words: CREB, CREM, Sympathetic ganglia, Apoptosis, Mouse
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INTRODUCTION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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).
The first mutation of the Creb gene (also known as Creb1
- Mouse Genome Informatics) realized in mice, the so-called
CREB
mutation, results in a viable hypomorphic allele
(Blendy et al., 1996;
Hummler et al., 1994). In
contrast to the CREB mutation, a null allele is
lethal at birth because of postnatal lung failure
(Rudolph et al., 1998). By
conditional mutagenesis the specific deletion of the Creb gene in
neural and glial precursors was achieved, and massive widespread apoptosis in
the embryonic brain was observed when these mutants were also Crem
deficient (Mantamadiotis et al.,
2002). Moreover, specific deletion of the Creb gene in
the postnatal forebrain resulted in selective and progressive
neurodegeneration of the striatum and part of the hippocampus in the absence
of CREM (Mantamadiotis et al.,
2002). Analysis of these mutants also revealed that compensatory
activities exist among these members of the CREB family
(Mantamadiotis et al.,
2002).
However, the cell-specific role of CREB in neuronal survival has not been
addressed. We have recently demonstrated by conditional ablation of CREB in
dopaminergic neurons only that the survival of dopaminergic neurons is weakly
affected and that CREM upregulation does not contribute to the phenotype
(Parlato et al., 2006).
To investigate the cell-specific role of CREB we used as a model developing
sympathetic neurons. The sympathetic neurons have been a classical model for
the study of the molecular mechanisms underlying neuronal survival activated
by target-derived neurotrophins
(Levi-Montalcini, 1987).
During embryonic development neurons are produced in excess and their survival
is controlled by the availability of target-derived growth factors. In many
areas of the nervous system, programmed cell death is the predominant
mechanism for determining mature neuron number. The final number of neurons is
thus dependent on the balance between signals leading to either cell death or
cell survival. In the peripheral nervous system this process to select
surviving neurons is, in part, dependent on the nerve growth factor (NGF),
acting through transcriptional regulation of gene expression.
A role for CREB in NGF-dependent survival has been clearly demonstrated for
the sensory ganglia (Lonze et al.,
2002). In vitro experiments performed on postnatal sympathetic
neuronal cultures indicated that NGF-dependent survival requires CREB-mediated
gene expression. These experiments also indicate that BCL-2 (also known as
BCL2 - Mouse Genome Informatics) could be the prosurvival effector of CREB
activity (Riccio et al.,
1999). However, it remains to be established whether these in
vitro observations reflect the role played by CREB in vivo in regulating the
survival of sympathetic neurons. Analysis of the neurons in the superior
cervical ganglia (SCG) of CREB knockout mice suggested the importance of CREB
in the survival of sympathetic neurons during embryonic development
(Lonze et al., 2002). However,
because the number of sympathetic neurons is already affected before the
acquisition of NGF-dependence for survival and the CREB protein is
ubiquitously ablated, the crucial role of CREB in mediating survival of
sympathetic neurons (Riccio et al.,
1999) could not be unequivocally established in vivo using CREB
knockout mice as a model (Lonze et al.,
2002). Prior to the requirement of NGF, recent genetic evidence
has indicated the importance of other extracellular cues, such as the glial
cell line-derived neurotrophic factor (GDNF) family member artemin
(Honma et al., 2002), in
sympathetic axon outgrowth and directed neuronal migration via GFR3
(Nishino et al., 1999) and RET
(Enomoto et al., 2001). Thus,
it is of great interest to analyze whether CREB-dependent signalling is of
crucial importance not only for NGF-dependent survival, but also at earlier
stages in the development and migration of sympathetic ganglia.
In order to investigate the role of CREB in developing sympathetic ganglia,
we generated mouse mutants in which the Creb gene is deleted
specifically in noradrenergic (NA) and adrenergic neurons of the central and
peripheral nervous system (Crebfl/fl; DBHCre mice,
abbreviated as CrebDBHCre) in a Crem-or
Atf-1-null genetic background. This specific mutation was made
possible because we had developed transgenic mice faithfully expressing the
Cre recombinase in cells under the control of the gene for
dopamine-ß-hydroxylase (DBHCre) using the PAC technology, which allows
position-independent expression of the transgene
(Casanova et al., 2001;
Parlato et al., 2006;
Wintermantel et al., 2002).
This Cre line has also been used for the specific inactivation of the gp130
signalling in sympathetic neurons (Stanke
et al., 2006).
The analysis of the specific ablation of CREB in comparison with the CREB knockout mice provides unexpected new insights into the cell-autonomous role of CREB, and demonstrates that loss of CREB unexpectedly results in neuroprotection.
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MATERIALS AND METHODS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), the coding sequence of the iCre, followed by the
bovine growth hormone polyadenylation signal, was introduced in-frame with the
ATG of the Dbh gene. The linear insert of 150 kb, carrying the
transgenic construct, was released by NotI digestion and separated by
pulse field gel electrophoresis. The male pronucleus of fertilized C57Bl/6
mice was injected with the DNA purified by agarase treatment and microdialysis
(Schedl et al., 1996).
Transgenic offspring was identified by dot blot and hybridization with a probe
specific for the iCre. To exclude the possibility that CREM or ATF-1 may compensate CREB, double-mutant mice were also generated crossing Creb+/fl;DBHCre+/- mice with Crem+/- or Atf-1+/- mice. The progeny of this first cross was then mated to yield F2 progeny of interest.
Crebfl/fl Crem-/- DBHCre+/-,
abbreviated as CREBDBHCre; CREM-/-, as well as
CrebDBHCre; Atf-1-/- mice are viable. The
statistical distribution of this and other genotypes remains close to the
expected values. The analysis of the genotype was performed as previously
described (Mantamadiotis et al.,
2002). iCre PCR primers were the following: forward
5'-CTGCCAGGGACATGGCCAGG-3'; reverse
5'-GCACAGTCGAGGCTGATCAGC-3'.
Histology, immunohistochemistry and in situ hybridization
For the detection of ß-galactosidase activity, embryos were processed
as described elsewhere (Hogan et al.,
1994).
For immunohistochemistry (IHC), embryos were fixed in 4% paraformaldehyde,
pH 7.2, overnight, processed for paraffin sections, sectioned at 7 µm and
stained with cresyl violet. For cryosections the samples were treated by 30%
sucrose in PBS, embedded in OCT and sectioned at 20 µm. For IHC the
following primary antibodies were used: anti-DBH (rabbit 1:500, DBH12-A; Alpha
Diagnostic), anti-Cre (rabbit 1:3000), anti-CREB (rabbit 1:3000), anti-CREM
(rabbit 1:500) (Mantamadiotis et al.,
2002), anti-tyrosine hydroxylase (TH) (sheep 1:500, AB1542;
Chemicon), anti-cleaved caspase-3 (Asp175) antibody (rabbit 1:800; Cell
Signalling Technology), anti-ATF-1 (rabbit 1:2000)
(Bleckmann et al., 2002), and
anti-p75 neurotrophin receptor (p75NTR) (rabbit 1:2000, AB1554;
Chemicon). The sections were incubated in citrate buffer, pH 6.0, and boiled
in a microwave oven. The primary antibodies were incubated overnight at
4°C. Biotin-conjugated secondary antibody was diluted 1:400 in PBS and
detection was performed using the avidin-biotin system (Vector Laboratories)
with the VECTOR peroxidase kit. The staining was developed with DAB and
H2O2 (Sigma) or with HistoGreen (Linaris). For double
immunolabeling with anti-TH and anti-activated caspase-3 antibodies, the
activity of the first antibody was blocked by the Avidin/Biotin blocking kit
(Vector Laboratories). Sections were stained as described for a single
antigen, and the second staining was performed with DAB, giving a blue
precipitate (Sigma).
Whole-mount TH immunostaining was performed as previously described
(Enomoto et al., 2001).
Non-radioactive in situ hybridization was performed on paraffin sections as
previously described (Parlato et al.,
2004). The expression of p75NTR mRNA was analyzed by
using two riboprobes recognizing the p75NTR intracellular domain or
the extracellular domain, respectively, as designed by McQuillen et al.
(McQuillen et al., 2002). The
expression pattern obtained with both riboprobes was similar, and therefore we
have shown only the experiments performed with the p75NTR
intracellular domain riboprobe.
Cell counts and statistical analysis
After caspase-3 immunolabeling, the sections were counterstained with
Nuclear Fast Red (Vector). Cell counts were performed at 40x
magnification in bright field. Clearly identified caspase-3-positive cells
characterized by brown colour were counted as positive in sections containing
the SCG and the stellate ganglia for both control and mutant mice. For area
and volume measurements, the IMAGE J program was used. The average number of
caspase-3-positive cells per mm2 was calculated for every fourth
section per ganglion, spanning the entire SCGs, in at least four sections per
side, because both SCGs were analyzed. Values shown are mean±s.e.m. for
at least four to five mice for each genotype. The volume of the SCG reported
is the mean±s.e.m. for both SCGs in at least four to five mice per
genotype. The total number of neurons per ganglia was determined by counting
the neurons with visible nuclei in every fourth section. The total counts were
quadrupled to calculate the total number of neurons. Values shown are
mean±s.e.m. Statistical significance was analyzed using a homoscedastic
Student's t-test. Values were considered significantly different with
*P<0.05 and ***P<0.001.
The average number of caspase-3-positive cells per section was also calculated for each animal. In this case, values are mean±s.e.m. for 12-15 sections per animal (both SCGs were analyzed in at least four to five mice of each genotype) (data not shown).
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RESULTS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). ß-galactosidase activity was revealed at E11.5
(Fig. 1B) in different regions
of the developing sympathetic chain (Fig.
1B), as depicted in the areas (i), (ii) and (iii). Positive
staining is also present in a region dorsolateral to the fourth ventricle
where the precursors of the locus coeruleus (LC), the major NA neurons of the
brain, are located (data not shown).
Mice in which exon 10 of the Creb gene is flanked by loxP sites
(floxed Creb allele; Crebfl)
(Mantamadiotis et al., 2002)
were crossed to DBHCre mice to generate Crebfl/fl;DBHCre
mutants (CrebDBHCre). CREB immunoreactivity is already
strongly reduced by E11.5 in the sympathetic chain of
CrebDBHCre mutants (data not shown). Some differences were
found in the sympathetic chain at E11.5, because neurons located in the
rostral part of the embryo show lower CREB expression compared with the caudal
part. This observation is consistent with the different timing in the
maturation of the sympathetic chain, which follows rostro-caudal patterning
(Hagedorn et al., 2000).
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Germline deletion of Creb results in aberrant morphology of the sympathetic chain
Because it is possible that the other member of the CREB family expressed
in the central nervous system, CREM, compensates for CREB loss, we decided to
generate mice that are CrebDBHCre; CREM-/-.
These mutants also survive after birth and show no reduced lifespan or
behavioural anomalies. The analysis of sympathetic ganglia, performed by IHC
with an antibody against TH, at E15.5, a developmental stage independent of
NGF for survival of sympathetic neurons, reveals that the SCG and the stellate
ganglion in CrebDBHCre; Crem-/-
(Fig. 3B,D) are properly shaped
and placed in comparison to control littermates
(Fig. 3A,C). At the same stage,
in Creb-null mice, the overall organization of the sympathetic
ganglia is severely affected, as shown in
Fig. 3F. At E17.5, a smaller
SCG in the Creb-null mutants, located in the cervical region
(Fig. 3G,H, area circled in
red), and a bigger stellate ganglion in the thoracic region
(Fig. 3G,H) is seen.
Specific ablation of Creb protects against developmentally regulated apoptosis
To analyze the physiological relevance of the absence of CREB specifically
in sympathetic neurons, we decided to analyze apoptotic neurons in the SCG and
the stellate ganglia at different developmental stages in controls,
Creb-null and CrebDBHCre; Crem-/-
mutants (Fig. 4). Although we
concentrate our studies on the SCG, which, because of its large size, its
accessibility and its vascular supply has been classically used as model
system to study survival of sympathetic neurons, similar observations were
also made in the stellate ganglia (data not shown).
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), and indeed in mice that lack NGF, neuronal loss can be
detected by E17.5 and at P0. This is associated with a 90% decrease in SCG
volume, indicating that NGF action on sympathetic neurons takes place in this
time window (Crowley et al.,
1994; Francis and Landis,
1999). At E17.5, as revealed using IHC for activated caspase-3 in
combination with the specific marker TH, the analysis of control embryos
reveals the presence of apoptotic cells in the SCG. In CREB-null mice
apoptotic cells are even more strongly represented
(Fig. 4B,E). In CREB-null mice,
it is not possible to clearly distinguish the SCG from the stellate ganglion,
therefore we have measured the total volume of the SCG and stellate ganglia,
identified by TH staining. Although no changes are revealed in the total
volume of stellate ganglia and SCG between controls and mutants at E17.5 (data
not shown), it is well possible that the increased apoptosis observed in the
Creb-null mice at this stage would postnatally result in a smaller
sympathetic ganglia. Surprisingly, in CrebDBHCre;
Crem-/- mutants, in contrast to CREB-null mice, there is no
increased apoptosis (Fig.
4C,F), rather a decrease in the number of caspase-3-positive cells
in the SCG, as summarized in Fig.
4G. In order to exclude the possibility of an earlier onset of
apoptosis in CrebDBHCre; Crem-/-, we searched
for the presence of apoptotic cells at E15.5, but undetectable levels of
apoptosis in the SCG characterize this early stage without significant
differences between genotypes (data not shown). Because the
CrebDBHCre; Crem-/- mutants, in contrast to the
germline CREB mutation, are not postnatally lethal, we determined the number
of caspase-3-positive cells at postnatal stages P0/P2 (n=4-5 per
genotype). We observe a reduced level of apoptosis in the control SCG in
comparison with E17.5 (Fig.
4G), with no changes in the CrebDBHCre;
Crem-/- mutants. When we measured the total volume of the SCG
at E17.5 there were no significant differences between controls and
CrebDBHCre; Crem-/- mutants
(Fig. 4H). At P0/P2 we found
that there is an overall increase in the size of the SCG, consistent with the
reduced number of apoptotic cells occurring at E17.5 in
CrebDBHCre; Crem-/-
(Fig. 4H). The number of SCG
neurons at P2 is significantly increased (control: 11014±1611;
CrebDBHCre; Crem-/- mutants: 19661±1905,
P<0.05). These results clearly indicate that the specific loss of
CREB in developing sympathetic neurons not only does not lead to decreased
neuronal survival, but unexpectedly has a protective effect against
developmentally regulated apoptosis.
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;
Mantamadiotis et al., 2002),
neither CREM nor ATF-1 play a crucial role in the survival of sympathetic
neurons.
p75NTR expression in sympathetic neurons depends on CREB
To shed light on the molecular mechanisms underlying the reduced levels of
apoptosis observed in the conditional CREB mutants, we reasoned that the
expression of crucial factors promoting developmental death of sympathetic
neurons might be CREB-dependent. It is well established that the
p75NTR plays an important role in promoting apoptosis of
sympathetic neurons lacking appropriate levels of target-derived
neurotrophins, such as NGF (Bamji et al.,
1998; Majdan and Miller,
1999). Interestingly, the phenotype of the CREB conditional
mutants is reminiscent of the phenotype of p75NTR-/- mice,
also showing an increase in the relative number of sympathetic neurons
(Brennan et al., 1999).
Therefore, we have analyzed by in situ hybridization the expression of several potential CREB target genes involved in the p75NTR-mediated signalling in sympathetic ganglia of control and CrebDBHCre; Crem-/- mutants at E17.5 (Fig. 6). At this developmental stage, we found that in the conditional mutants (Fig. 6B) the levels of p75NTR mRNA are much lower than in control embryos (Fig. 6A), whereas they are unaltered in other regions not affected by the mutation, such as the cholinergic neurons of the basal forebrain (Fig. 6C,D and data not shown). The reduced level of p75NTR protein in the CrebDBHCre; Crem-/- mutants (Fig. 6F) in comparison with control littermates (Fig. 6E) probably accounts for the inhibition of developmentally regulated apoptosis observed in sympathetic ganglia of the conditional CREB mutant.
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DISCUSSION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This analysis revealed that increased cell death is associated with misplacement of sympathetic ganglia in the CREB germline mutant. Because both effects are not observed in the conditional mutant, CREB expression in cells other than sympathetic neurons is required for neuronal survival and migration. The characterization of the conditional mutant reveals a novel distinct effect in neuronal survival upon loss of CREB. Indeed, reduced levels of developmentally regulated apoptosis are found in the sympathetic ganglia, resulting in an increased number of sympathetic neurons. This effect is correlated with reduced activation of caspase-3 and downregulation of the p75NTR, a signal mediator necessary for apoptosis in sympathetic neurons.
Germline loss of CREB results in misplacement and reduced survival of sympathetic neurons
The results presented in our study are summarized in
Fig. 7 by a schematic model of
the sympathetic neuron development in wild type and in the different CREB
mutants analyzed here. Developing wild-type neurons successfully reaching
their targets survive in the presence of an optimal supply of pro-survival
factors. Here, we oversimplify considering that NGF, secreted by the targets
of sympathetic ganglia during the period of target competition, plays a major
role in defining the final number of surviving sympathetic neurons. In
Creb-/- mutants, CREB expression is lost in developing
neurons, as well as in target cells. Loss of CREB in target cells may be
primarily responsible for the migrational deficit of the SCG neurons, and
hence responsible for the increased apoptosis in sympathetic neurons in the
absence of proper survival signals originating in target cells. Developing
sympathetic neurons, prior to NGF action, require migrational cues to
establish their final position (Glebova
and Ginty, 2005). Interestingly, gene targeting studies revealed
that mice deficient in RET (Enomoto et al.,
2001) or its cofactor GFR3
(Nishino et al., 1999) or the
ligand artemin exhibit severe defects in the SCG
(Honma et al., 2002) during
the period from E12.5 to E13.5. As in Creb-null mice, the SCG is
found caudal to its normal location in all these mutants, because neuronal
precursors of the sympathetic system fail to migrate and to project axons
properly. These primary deficits lead to mis-routing of sympathetic nerve
trunks and accelerated cell death of sympathetic neurons later in development.
Because CREB phosphorylation is not only driven by NGF, but also by GDNF via
its receptor tyrosine kinase RET involving the Ras/ERK pathway for activation
(Hayashi et al., 2000), this
signalling pathway could be affected by loss of CREB. The fact that in the
conditional mutant, the SCG is correctly positioned, despite early loss of
CREB, strongly suggests that CREB expression is required in cells other than
neurons for proper development of sympathetic ganglia. Because in null mutants
CREB ablation also occurs in cells other than neurons, extraneuronal cues may
depend on CREB for their expression.
A cell-autonomous role of CREB in survival of sympathetic neurons is indicated by the conditional mutant
In the sympathetic ganglia of the conditional mutants lacking CREB only in
NA neurons, we evaluate the cell-autonomous role of CREB activity in
pro-survival and pro-apoptotic pathways, because the neurotrophic supply from
target organs is probably unaffected. Previous work performed on postnatal
sympathetic neuronal cultures in which CREB-mediated gene expression is
abolished by the use of a dominant-negative protein indicates that all three
CREB family members contribute to the survival of sympathetic neurons
(Riccio et al., 1999).
In the present study we focused on developmentally regulated cell death and
we observed that in the conditional CREB mutants lacking either CREM or ATF-1,
this process is inhibited, as evidenced by the reduced number of activated
caspase-3-positive cells in sympathetic ganglia. Despite what has been
previously shown in other CREB mutants regarding the possibility of
compensation by other family members
(Bleckmann et al., 2002;
Mantamadiotis et al., 2002),
loss of CREB and CREM or ATF-1 does not result in a more severe impairment of
cell survival (Fig. 5).
Although neither CREM nor ATF-1 is expressed in sympathetic ganglia from
controls and conditional mutants at E17.5 (data not shown), we cannot rule out
the possibility that inactivation of all three transcription factors would
result in increased cell death. The generation of transgenic mice expressing a
dominant-negative CREB protein exclusively in sympathetic neurons could
represent a valuable tool to address this issue.
To our knowledge, this is the first example of mutants in which CREB
ablation leads to protection against cell death. Several hypotheses can be
taken into account to explain this observation. An imbalance between
pro-apoptotic signals and pro-survival signals during such a crucial
time-window could result in an increased number of surviving sympathetic
neurons. It has been indicated that CREB may regulate a pro-survival factor,
such as Bcl-2 (Lonze and Ginty,
2002; Riccio et al.,
1999). However, although in vitro experiments established that
Bcl-2 is an important regulator of survival of sympathetic neurons after NGF
deprivation (Greenlund et al.,
1995), inactivation of Bcl-2 itself in mouse mutants
(Michaelidis et al., 1996) did
not result in increased death of sympathetic neurons during naturally
occurring cell death starting at E16-E17 in mice
(Coughlin and Collins,
1985).
Interestingly, the phenotype of the CREB conditional mutants is reminiscent
of the phenotype of Bdnf-/- mice
(Bamji et al., 1998), showing
an increase in the relative number of sympathetic neurons. The brain-derived
neurotrophic factor (BDNF) is a well-characterized CREB target
(Shieh and Ghosh, 1999;
Shieh et al., 1998;
Tao et al., 1998). This
neurotrophin may play a dual role in the fate of developing neurons, either
promoting their survival or their apoptotic death. In sympathetic neurons,
BDNF signalling may inhibit axonal growth and neuronal survival through the
p75NTR, because its receptor TrkB is not expressed in sympathetic
neurons (Bibel and Barde,
2000). In vitro experiments indicate that, when sympathetic
neurons are exposed to suboptimal survival signals, activation of
p75NTR by BDNF leads to neuronal apoptosis. Although p75 signalling
mechanisms remain poorly understood, loss of such a mechanism during the
period of cell death could explain the increased number of sympathetic neurons
observed in the Bdnf-/- mice
(Bamji et al., 1998) and in
p75NTR-/- mice (Brennan
et al., 1999). The similarity between phenotypic alterations
suggests a correlation between CREB and BDNF/p75NTR signalling.
Interestingly, the p75NTR gene is included, among other signalling
molecules, in a comprehensive study aiming to identify CREB targets by an
approach based on chromatin immunoprecipitation and a modification of SAGE
(Impey et al., 2004). Although
the functional role of CREB in regulating p75NTR gene expression
has not been demonstrated, our finding that lower levels of p75NTR
expression are shown in developing sympathetic neurons of the conditional CREB
mutants, indicates that CREB is required for p75NTR expression.
Consequently, lower levels of p75NTR expression leads to decreased
apoptosis, resulting in enlarged sympathetic ganglia after birth.
In summary, we conclude that CREB expression in cells other than sympathetic neurons is required for proper shaping of the sympathetic chain and for controlling neuronal survival, as illustrated by the comparison between germline and conditional Creb mutants. Indeed, loss of CREB in developing sympathetic neurons neither affects their position nor impairs their survival. Unexpectedly, loss of CREB exclusively in developing sympathetic neurons results in a protective effect against developmentally regulated apoptosis because of downregulation of p75NTR expression.
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ACKNOWLEDGMENTS |
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Footnotes |
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Present address: Gynecology and Andrology, Schering AG, Berlin, Germany
Present address: Department of Gastroenterology, Hannover Medical School,
Hannover, Germany
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