School of Biosciences, Biomedical Building, Museum Avenue, PO Box 911, Cardiff, CF10 3US, Wales
Author for correspondence (e-mail:
humberto.g{at}ed.ac.uk)
Accepted 5 January 2005
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SUMMARY |
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Key words: NF-B, Axon, Dendrite, BDNF, Pyramidal neuron, Sensory neuron, Mouse
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Introduction |
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In the nervous system, NF-B is widely expressed
(Bhakar et al., 2002
;
O'Neill and Kaltschmidt, 1997
;
Yalcin et al., 2003
) and is
activated by a variety of neurotrophic factors, cytokines and
neurotransmitters (Carter et al.,
1996
; Guerrini et al.,
1995
; Hamanoue et al.,
1999
; Kaltschmidt et al.,
1995
; Yalcin et al.,
2003
). NF-
B can promote neuronal survival and protect
neurons from toxic insults (Bhakar et al.,
2002
; Bui et al.,
2001
; Daily et al.,
2001
; Digicaylioglu and
Lipton, 2001
; Fridmacher et
al., 2003
; Lipsky et al.,
2001
; Mattson et al.,
2000
; Piccioli et al.,
2001
; Tamatani et al.,
2000
; Yu et al.,
2000
) but can also play a role in bringing about neuronal death
(Pizzi et al., 2002
;
Shou et al., 2002
). It has
been implicated in adaptive responses to inflammatory conditions and
neurodegenerative disorders (Bhakar et al.,
2002
; Blondeau et al.,
2001
; Clemens et al.,
1997
; Fridmacher et al.,
2003
; Gabriel et al.,
1999
; Gentry et al.,
2000
; Grilli and Memo,
1999
; Guerrini et al.,
1995
; Mattson et al.,
2000
), and participates in peripheral nerve myelination
(Nickols et al., 2003
). Recent
studies have shown that NF-
B might also play an important role in
neural-specific functions. NF-
B is activated in hippocampal neurons and
cerebellar granule cells in response to N-methyl-d-aspartate receptor
occupancy by glutamate (Guerrini et al.,
1995
; Meffert et al.,
2003
; Scholzke et al.,
2003
). Treatment of hippocampal slices with
B decoy DNA
prevents induction of long-term depression and significantly reduces long-term
potentiation (Albensi and Mattson,
2000
). Pharmacological inhibition of NF-
B activation
interferes with memory formation in the crab
(Merlo et al., 2002
), and mice
lacking p65 exhibit a deficit in spatial learning
(Meffert et al., 2003
).
NF-
B is also required for consolidation of fear conditioning in the
amygdala (Yeh et al.,
2002
).
In addition to activity-induced changes in synaptic function, the
elaboration and modification of neuronal processes is thought to be an
important anatomical change underlying learning and memory. To investigate if
NF-B is involved in regulating the growth and morphology of neural
processes in development, we studied the activation and role of NF-
B in
two well-characterized populations of developing peripheral and central
neurons. Sensory neurons of the embryonic and postnatal mouse nodose ganglion
survive and extend neurites in dissociated cell culture supplemented with
brain-derived neurotrophic factor (BDNF)
(Davies et al., 1993
) and
layer 2 pyramidal neurons of the mouse somatosensory cortex elaborate
extensive dendritic arbors in organotypic slice cultures established in the
postnatal period (Gutierrez et al.,
2004
; Niblock et al.,
2000
). Here we show that preventing NF-
B activation or
inhibiting NF-
B transcriptional activity reduces process growth and
complexity in both neuronal models.
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Materials and methods |
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Cortical slice cultures
Vibrotome slices (300 µm) of P6 or P7 CD1 mouse cerebrum were cut in the
coronal plane in cold (4°C) artificial cerebrospinal fluid (160 mmol/l
NaCl, 200 mmol/l KH2PO4, 5 mmol/l KCl, 1 mmol/l
MgSO4, 33 mmol/l glucose, 10 mmol/l HEPES, 1 mmol/l
CaCl2). The slices were cultured in 35 mm Petri dishes on 0.4 µm
Millicel inserts (Millipore) floating on 1 ml of culture medium (50%
Dulbecco's Minimal Essential Medium, 25% heat-inactivated horse serum, 25%
Hank's Balanced Salt Solution, 6.5 mg/ml glucose and 100 U/ml streptomycin and
penicillin). The cultures were incubated in 5% CO2 at 37°C.
Ballistic transfection
Ballistic transfection of dissociated neurons and cortical slices was
carried out using a hand-held gene gun (Helios Gene-gun, BioRad Hercules, CA
USA). Gold particle cartridges were prepared using the manufacturer's
protocol. Briefly, 20 mg of 1.6 µm gold particles were suspended in 100
µl of 50 mmol/l spermidine and 20 µg of pYFP (Clontech) together with
either pSR-IB-
or pCDNA control plasmid. The gold particles were
precipitated with 100 µl of 2 mol/l CaCl2, washed three times
with 100% ethanol, resuspended in 1.2 ml of 100% ethanol plus 0.01 mg/ml
polyvinylpirrolidone and loaded into Teflon tubing.
Double-stranded B Decoy DNA was prepared by annealing complementary
single stranded oligonucleotides of the following sequences:
5'-GAGGGGACTTTCCCT-3' and 5'-AGGGAAAGTCCCCTC-3'.
Control DNA with a scrambled sequence was prepared by annealing the following
sequences: 5'-GATGCGTCTGTCGCA-3' and
5'-TGCGACAGACGCACT-3'. Double-stranded DNA solutions were prepared
at a concentration of 50 mmol/l and ethanol precipitated onto the gold
microcarriers along with either the pYFP or pRFP reporter plasmid. In the case
of cortical slice cultures, control and
B decoy DNA-coated particles
were mixed prior to loading into the Teflon tubing.
For transfecting nodose neurons, between 1000 and 3000 neurons were plated in a 50 µl droplet of defined medium in the centre of a 35 mm diameter tissue culture dish that had been pre-coated with poly-ornithine (0.5 mg/ml, overnight) and laminin (20 µg/ml for 3 hours). Neurons were incubated at 37.5°C in a humidified 3.5% CO2 incubator for 3-4 hours to allow the cells to attach, and the medium was removed from the dish just before transfection. The coated gold particles were shot into the cultured neurons with the gun pressurized at 200 psi. A 70 µm nylon mesh screen was placed between the gun and the culture to protect the cells from the shock wave. After transfection, 2 ml of defined medium with or without 10 ng/ml BDNF was added to the culture dishes.
For transfecting cortical neurons, gold particles were shot into slices at a pressure 250 to 300 psi. A 70 µm nylon mesh screen was also used to protect the tissues from the shock wave. After transfection, the slices were incubated in medium with or without 10 ng/ml BDNF for 48 hours before the dendritic arbors of transfected pyramidal neurons were imaged.
Quantification of fluorescence
To estimate the relative level of NF-B activation in cultured
neurons under different experimental conditions, the neurons were transfected
with a plasmid expressing GFP under the control of an NF-
B promoter.
Neurons were imaged with a Zeiss Axioplan laser scanning confocal microscope.
The mean fluorescence intensity for each soma was obtained using LSM510
software, based on the standard 255 intensity level scale after subtraction of
background intensity. Between 40 and 60 neurons were imaged for each
experimental condition and all imaging and quantification was performed blind.
Statistical comparisons were performed using simple ANOVA followed by Fisher's
post-hoc test.
Estimates of neuronal survival in dissociated cultures
For estimating the survival of transfected neurons, cultures were shot with
the gene gun 3 hours after plating and YFP-labelled neurons were counted 12
hours after plating and again at 48 hours. The number of labelled neurons
surviving at 48 hours was expressed as a percentage of the initial number of
labelled neurons. The area counted was defined by the area in which gold
particles could be seen to be embedded in the bottom of the culture dish.
Triplicate cultures were set up for all conditions and the data shown are
compiled from two to four separate experiments for each age.
Estimates of neuronal survival in cultures that were not transfected with the gene gun were made by counting the number of neurons in a 12 x 12 mm grid in the centre of the dish 3 to 6 hours after plating and again at 48 hours. The number of neurons surviving at 48 hours was expressed as a percentage of the initial number of neurons.
Analysis of nodose neuritic arbors
Transfected YFP-labelled neurons were visualized and digitally acquired
using an Axioplan Zeiss laser scanning confocal microscope. For experiments in
which neurons were not transfected with YFP, they were first fluorescently
labelled for expression of the neuron-specific marker ß-III tubulin. For
this, the cells were rinsed with PBS at room temperature, fixed in 4%
paraformaldehyde/PBS for 30 minutes at room temperature, rinsed twice with PBS
and subsequently permeabilized and blocked with 5% bovine serum albumin and
0.1% Triton X-100 in PBS for 60 minutes at room temperature. The cells were
incubated with monoclonal anti-ßIII tubulin antibodies (1:1000, Promega)
overnight at 4°C, rinsed three times with PBS and incubated with
FITC-labelled rabbit anti-mouse IgG secondary antibody (Molecular Probes, Inc,
Eugene, OR, USA) for 1 hour at room temperature.
For every condition studied, between 40 and 70 neurons were captured, and
neuritic arbors were traced using LSM510 software. These traces were used to
ascertain total neurite length and number of branch points. Sholl analysis was
also carried out on these traces. For this, concentric, digitally generated
rings, 30 µm apart were centred on the cell soma, and the neurites
intersecting each ring were counted
(Sholl, 1953). Pair-wise
comparisons were made using the Student t-test. For multiple
comparisons, ANOVA was performed followed by Fisher's post-hoc test.
Analysis of pyramidal dendrites
Layer II/III pyramidal neurons of the somatosensory cortex were studied
with an Axioplan Zeiss laser scanning confocal microscope 48 hours after
transfection. The slices were fixed for 30 minutes with 4% paraformaldehyde in
PBS, and DAPI counterstaining was used to confirm the laminar localization.
For every experimental condition studied, the dendritic organization of
between 50 and 60 neurons was reconstructed and analysed. For each neuron, 15
and 20 optical sections were obtained using 20x and 40x water
immersion objectives. Three-dimensional projections were generated by merging
the resulting Z stacks, and the dendritic arbors were traced using LSM510
software. Neurons tracings were analysed using a customized Matlab script for
the automatic counting of branching points, number of primary dendrites,
dendritic length and other topological parameters. Sholl analysis was carried
out directly on the Z-stack images. In this case, concentric, digitally
generated rings, 15 µm apart were centred on the cell soma, and the
dendrites intersecting each ring were counted
(Sholl, 1953). Statistical
analysis was carried out as described above.
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Results |
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Given the well-known involvement of NF-B in regulating cell
survival, we first assessed the effect of the super-repressor
I
B-
on the survival of neonatal nodose ganglion neurons. Three
hours after plating, P1 nodose neurons were transfected with either the
super-repressor I
B-
plasmid or control plasmid and half the
culture dishes were supplemented with BDNF. Transfection was carried out by
firing plasmid-coated gold particles into cultures using the Helios gene gun.
To identify the transfected neurons and outline their neurite arbors, the gold
particles were also coated with a YFP expression plasmid. Twelve hours after
plating, when all transfected neurons had become clearly recognizable by the
expression of YFP, the total numbers of transfected neurons were counted.
Forty-eight hours after plating, the surviving labelled neurons were counted
and expressed as a percentage of the numbers counted at 12 hours.
Fig. 1 shows a representative
sample of reconstructed newborn nodose neurons grown in the presence of BDNF.
The illustrated neurons in the upper row represent the range of morphologies
observed in P1 control transfected cultures. A corresponding sample of
super-repressor I
B-
transfected cultures is shown in the lower
row. Fig. 2A shows that 80% of
neurons were surviving with BDNF at this time and that there was no
significant difference in the numbers of super-repressor I
B-
transfected neurons and control transfected neurons surviving with this
neurotrophin. Only 40% of the neurons survived for 48 hours without BDNF
(Fig. 2A), and transfection of
these neurons with super-repressor I
B-
did not further reduce
their survival (data not shown). These results indicate that preventing
NF-
B activation with super-repressor I
B-
does not affect
the survival of P1 nodose neurons, either in the presence or in the absence of
BDNF.
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|
NF-B transcriptional activity in nodose neurons is unaffected by BDNF
To determine if NF-B transcriptional activity is influenced by BDNF,
we transfected newborn nodose neurons with a reporter construct in which GFP
is under the control of an NF-
B promoter. Transfected neurons were
positively identified by co-transfection with an RFP expression plasmid.
Neurons were shot 3 hours after plating with gold particles coated with both
these plasmids together with either the super-repressor I
B-
plasmid or corresponding empty control plasmid and were incubated for a
further 12 hours with or without BDNF. Twelve hours were chosen because at
this time most neurons still survive even in the absence of BDNF.
Fig. 3A shows that neurons
transfected with the control plasmid exhibited a clear GFP signal, whereas
neurons transfected with the super-repressor I
B-
plasmid
exhibited a weak GFP signal. Quantification
(Fig. 3B) revealed a
statistically significant five-fold reduction in average GFP fluorescence in
super-repressor I
B-
-transfected neurons compared with
control-transfected neurons, confirming that super-repressor I
B-
effectively reduces NF-
B-dependent gene expression. However, there was
no significant difference in the level of GFP fluorescence in
control-transfected neurons grown with or without BDNF, and the GFP signal was
reduced to the same extent by super-repressor I
B-
in the
presence and absence of BDNF.
|
Super-repressor IB-
reduces neurite growth in a developmentally dependent manner
To ascertain whether the inhibitory effect of the super-repressor
IB-
on neurite growth occurs over a particular stage of
development, we established cultures of nodose neurons over a range of
embryonic and postnatal stages. These neurons were grown with BDNF and
transfected with either the super-repressor I
B-
plasmid and pYFP
or the control plasmid and pYFP. From the youngest age at which neurons could
be effectively transfected using the gene gun (E16) to the latest age studied
(P3), neuron counts after 48 hours incubation demonstrated that the
super-repressor I
B-
did not affect the ability of the neurons to
survive with BDNF (Fig. 4A).
Quantification of total neurite length and branch point number
(Fig. 4B,C) revealed that
super-repressor I
B-
had no significant effect on neurite growth
at E16 and P3. However, at intermediate stages it caused highly significant
reductions in length and branching that were maximal at P0, where 43 and 48%
reductions were observed, respectively. Likewise, Sholl analysis revealed that
super-repressor I
B-
caused significant reductions in the size
and complexity of neurite arbors at E18, P0 and P1, with a maximal effect at
P0 (Fig. 4D-H). To investigate
if NF-
B activation plays any role on neurite growth at stages prior to
E16, we crossed mice that were heterozygous for a null mutation in the
p65 gene to generate p65-deficient and wild-type embryos. Cultures
were established from these embryos at E14, the oldest age to which
p65-deficient embryos survive, and neurite growth was quantified after 24
hours incubation in medium containing BDNF. These experiments revealed no
significant differences in neuronal survival, neurite length, branch number
and branching with distance from the cell body between wild-type and
p65-deficient neurons (data not shown). Taken together, the above results
suggest that NF-
B activation impairs neurite growth only during a
restricted window of development encompassing late embryonic and early
neonatal stages.
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As in studies of cultured nodose neurons, we wished to ascertain whether
inhibiting NF-B activation in pyramidal neurons affected their survival
in cortical slices. For this, we transfected cortical slices with a YFP
plasmid together with either the super-repressor I
B-
plasmid or
an empty plasmid and counted the total number of labelled neurons in layers 2
and 3 of the somatosensory cortex 24 hours after transfection (when labelled
pyramidal neurons were clearly discernible) and again 48 hours after
transfection. There was no significant difference in the number of labelled
neurons 48 hours after transfection, expressed as a percentage of the number
of labelled neurons 24 hours after transfection in control-transfected slices
(60.1±7.9%, n=11 separate cultures) and super-repressor
I
B-
-transfected slices (70.0±5.6%, n=16 separate
cultures). Similar results were obtained when NF-
B-dependent
transcription was blocked with
B decoy DNA (79.5±4.3,% survival,
n=18 separate cultures) compared with control DNA transfected neurons
(83.6±5.6% survival, n=14 separate cultures). These data
suggest that inhibiting NF-
B activation does not affect the survival of
pyramidal neurons in cortical slices.
Fig. 9B,C shows that the
super-repressor IB-
caused significant reductions in the number
of branch points of pyramidal neuron dendritic arbors and the overall length
in these arbors compared with control-transfected neurons. Accordingly, Sholl
analysis revealed that the super-repressor I
B-
caused
significant reductions in dendritic branching between 30 and 120 µm from
the cell body (Fig. 9A). The
typical appearances of I
B-
-transfected and control-transfected
pyramidal neurons are shown in Fig.
9D. Neurons expressing
B decoy DNA showed very similar
significant decreases in overall dendritic branching
(Fig. 9F) and length
(Fig. 9G) compared with neurons
expressing the scrambled
B control DNA, and Sholl analysis likewise
revealed significant reductions in dendritic branching between 30 and 120
µm from the cell body in
B decoy-expressing neurons
(Fig. 9E). The typical
appearances of pyramidal neurons transfected with
B decoy DNA and
scrambled control DNA are shown in Fig.
9H. Taken together, these results show that blocking NF-
B
activation with either super-repressor I
B-
or
B decoy DNA
significantly impairs the growth layer 2/3 pyramidal neuron dendrites in
neonatal cortical slice cultures.
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Discussion |
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Analysis of the effect of super-repressor IB-
at different
developmental stages revealed that NF-
B affects neurite growth and
morphology only during a restricted period of development between E18 and P1.
This period occurs at the latter end of the phase of naturally occurring
neuronal death in cranial sensory ganglia when the peripheral and central
axons of the remaining neurons are establishing and refining their terminal
arborizations (Davies and Lumsden,
1984
). Thus it is possible that NF-
B plays a role in
modulating the growth and branching of axonal terminals in the target fields
of sensory neurons during this critical period of development when functional
connections are being established.
In addition to its influence on peripheral sensory neurites, NF-B
signalling also regulates the size and complexity of the dendritic arbors of
layer 2-3 pyramidal neurons in the postnatal mouse somatosensory cortex. Both
super-repressor I
B-
and
B decoy DNA each caused highly
significant reductions in the overall dendrite length, total branch number and
branching with distance from the cell body in cortical slices established from
P3 and P4 mice. This was observed at a stage in development when the dendritic
arbors of these neurons are growing rapidly and establishing functional
connections. Taken together, these findings reveal that NF-
B signalling
influences the growth of neural processes in at least two populations of
neurons in the developing peripheral nervous system (PNS) and central nervous
system (CNS).
We have shown that NF-B is activated at a certain basal level in
cultured nodose neurons independently of BDNF. This basal level of NF-
B
activity is maximal for neurite growth because augmenting NF-
B
transcriptional activity by overexpressing p65 causes no further increase in
neurite growth. Overexpression of p65 does, however, enhance the survival of
nodose neurons grown without neurotrophic factors as effectively as BDNF.
Likewise, overexpression of p65 in trigeminal sensory neurons grown without
neurotrophic factors promotes their survival just as well as NGF
(Hamanoue et al., 1999
). Taken
together, these findings suggest that different thresholds of NF-
B
activity enhance neurite growth and neuronal survival. What drives the basal
level of NF-
B transcriptional activity in cultured nodose neurons is
unclear. This may be constitutive or secondary to activation of receptors for
neurotrophic factors or cytokine receptors. While exogenous factors can be
excluded because it occurs in defined medium, neurotrophic factors or
cytokines could be produced in culture by the neurons themselves or by some
residual non-neuronal cells.
In addition to intrinsic developmental programmes that establish certain
characteristic morphological features of the dendritic and axonal architecture
of different kinds of neurons, a wide variety of extrinsic signals regulate
the growth of neural processes, including neurotransmitters, growth factors,
extracellular matrix proteins and an assortment of guidance molecules. These
extrinsic signals variously engage several intracellular signalling pathways
to influence process growth, including Ras-MEK-ERK, PI 3-kinase-Akt and
calcium/calmodulin kinases. Activation of these pathways influences the
dynamics of the neuronal cytoskeleton in a variety of ways to control axonal
and dendritic growth. For example, by phosphorylating microtubule-associated
proteins and by regulating the activity of the Rho family of GTPases and their
effectors, which in turn regulate the structure and dynamics of the actin
cytoskeleton (Fink and Meyer,
2002; Lundquist,
2003
; Miller and Kaplan,
2003
). CREB and NeuroD have also been implicated in mediating the
effects of calcium/calmodulin kinases on dendritic growth
(Gaudilliere et al., 2004
;
Redmond et al., 2002
),
although the target genes that mediate the effects of these transcription
factors on dendrites are not known. It has also been reported that inhibiting
NF-
B in PC12 cells decreases the proportion of cells that possess
neurites following TrkA activation (Foehr
et al., 2000
). However, it is unclear whether this result reflects
a direct influence of NF-
B signalling on neurite growth per se or
represents one of the downstream consequences of TrkA-induced differentiation
of these tumour cells.
Of the multitude of genes induced by NF-B in various cell types,
several encode cell adhesion molecules and other proteins that influence cell
migration (Pahl, 1999
), some
of which could be potentially relevant for process growth in neurons. For
example, activity-dependent upregulation of NCAM on cultured striatal neurons
depends on NF-
B activation (Simpson
and Morris, 2000
). NCAM is widely expressed on the dendrites and
axons of a variety of neurons in the developing brain, and becomes
progressively localized to synapses with age
(Butler et al., 1998
;
Chung et al., 1991
;
Fox et al., 1995
;
Persohn and Schachner, 1990
).
NCAM stimulates neurite growth from many kinds of neurons in vitro
(Skaper et al., 2001
).
Clustering of NCAM on cultured cerebellar neurons leads to activation of MAP
kinase (Schmid et al., 1999
),
and MAP kinase activation has been shown to promote the growth of hippocampus
and sympathetic dendrites (Vaillant et
al., 2002
; Wu et al.,
2001
). Tenascin-C is also an NF-
B-regulated protein
(Mettouchi et al., 1997
) that
is a prominent component of the neural extracellular matrix, where it plays
important roles in regulating neurite outgrowth and guidance during
development (Joester and Faissner,
2001
). Although tenascin-C is expressed predominantly by glial
cells in the PNS and CNS, several populations of neurons also express
tenascin-C during development, when its regulation might influence process
growth. For example, tenascin-C is transiently expressed by subsets of neurons
in the embryonic hippocampus (Ferhat et
al., 1996
) and postnatal spinal cord
(Zhang et al., 1995
). ß1
integrin is another NF-
B-regulated protein
(Wang et al., 2003
). ß1
integrin dimerizes with several different
integrin subunits to form
receptors for many extracellular matrix components, including laminins
(Previtali et al., 2001
).
Interaction between laminin and
1ß1 or
3ß1 integrins
expressed on the growth cone promotes the growth of sensory and sympathetic
neurites in culture (DeFreitas et al.,
1995
; Schmidt et al.,
1995
; Tomaselli et al.,
1993
), and anti-integrin ß1 antibody in combination with
anti-L1 and anti-N-cadherin reduces the growth of ciliary ganglion neurons on
Schwann cells (Bixby et al.,
1988
).
In summary, we have characterized a function of NF-B signalling that
differs markedly from its well-established ubiquitous role in immune and
stress responses and regulation of apoptosis. Our demonstration that
NF-
B transcriptional activity promotes the growth and branching of
axonal and dendritic processes in the developing PNS and CNS furthers our
understanding of the molecular mechanisms that establish and refine neural
connections during development and has potentially important implications for
the involvement of NF-
B in learning and memory.
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ACKNOWLEDGMENTS |
---|
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Footnotes |
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Present address: Lab Anatomia patologica-genetica, Hospital Arnau de
Vilanova, Av Rovira Rourre, 80, 25198 Lleida, Spain
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