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The Journal of Neuroscience, July 1, 1999, 19(13):5429-5434
Developmental Requirement of gp130 Signaling in Neuronal Survival
and Astrocyte Differentiation
Kinichi
Nakashima1, 2,
Stefan
Wiese3,
Makoto
Yanagisawa1,
Hirokazu
Arakawa1,
Naoki
Kimura1,
Tatsuhiro
Hisatsune4,
Kanji
Yoshida5,
Tadamitsu
Kishimoto6,
Michael
Sendtner3, and
Tetsuya
Taga1
1 Department of Molecular Cell Biology and
2 Cell Fate Modulation Research Unit, Medical Research
Institute, Tokyo Medical and Dental University, Tokyo, 101-0062,
Japan, 3 Clinical Research Unit for Neuroregeneration,
Department of Neurology, University of Würzburg, Würzburg,
97080, Germany, 4 Division of Integrated Biosciences,
Graduate School for Frontier Science, The University of Tokyo, Tokyo,
113-8657, Japan, and 5 Department of Molecular Immunology,
Research Institute for Microbial Diseases, 6 Osaka
University, Osaka, 565-0871, Japan
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ABSTRACT |
gp130 is a signal-transducing receptor component used in common by
the interleukin-6 (IL-6) family of hematopoietic and neurotrophic cytokines, including IL-6, IL-11, leukemia-inhibitory factor, ciliary
neurotrophic factor, oncostatin-M, and cardiotrophin-1. We have
examined in this study a role of gp130 in the nervous system by
analyzing developmental cell death of several neuronal populations and
the differentiation of astrocytes in gp130-deficient mice. A
significant reduction was observed in the number of sensory neurons in
L5 dorsal root ganglia and motoneurons in the facial nucleus,
the nucleus ambiguus, and the lumbar spinal cord in gp130  / mice on
embryonic day 18.5. On the other hand, no significant neuronal loss was
detectable on day 14.5, suggesting a physiological role of gp130 in
supporting newly generated neurons during the late phase of development
when naturally occurring cell death takes place. Moreover, expression
of an astrocyte marker, GFAP, was severely reduced in the brain of
gp130 / mice. Our data demonstrate that gp130 expression is
essential for survival of subgroups of differentiated motor and sensory
neurons and for the differentiation of major populations of astrocytes
in vivo.
Key words:
gp130; deficient mice; cytokine; astrocyte; motor neuron; sensory neuron
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INTRODUCTION |
The interleukin-6 (IL-6) family of
cytokines, i.e., IL-6, IL-11, leukemia inhibitory factor (LIF), ciliary
neurotrophic factor (CNTF), oncostatin-M (OSM), and
cardiotrophin-1 (CT-1), display an array of biological functions (Taga
et al., 1989 ; Kishimoto et al., 1994; Taga and Kishimoto, 1997). All
these cytokines use gp130 in their respective receptor complexes as a
signal-transducing component (Taga et al., 1989, 1992; Kishimoto et
al., 1994; Stahl and Yancopoulos, 1994; Taga and Kishimoto, 1997),
which explains their functional overlaps. These cytokines signal
through either homodimers of gp130 (for IL-6 and IL-11) or heterodimers
comprising gp130 and a dimer partner, such as an LIF receptor
(LIFR) (for LIF, CNTF, OSM, and CT-1) and an OSM-specific receptor
component (OSMR) (for OSM) (Davis et al., 1993; Murakami et al., 1993;
Kishimoto et al., 1994; Taga and Kishimoto, 1997).
Mice lacking IL-6, LIF, or CNTF displayed phenotypes less severe than
expected from pleiotropic nature of each cytokine, presumably because
of compensation by the remaining gp130-stimulating cytokines (Stewart et al., 1992; Escary et al., 1993; Masu et al., 1993; Kopf et
al., 1994). In contrast, mice lacking gp130 or LIFR die during
development or shortly after birth (Li et al., 1995; Ware et al., 1995;
Yoshida et al., 1996, 1998; Kawasaki et al., 1997). gp130-deficient
mice exhibit defects in myocardium and hematopoiesis (Yoshida et al.,
1996, 1998). Mice deficient for gp130 or LIFR show placental defects
and reduced bone mass (Ware et al., 1995; Kawasaki et al., 1997;
Yoshida et al., 1998).
Within the nervous system, LIF, CNTF, CT-1, and OSM support survival of
several types of neurons in vitro (Ernsberger et al., 1989;
Martinou et al., 1992; Taga, 1996; Horton et al., 1998). They induce
cholinergic properties in cultured autonomic neurons (Yamamori et al.,
1989; Patterson, 1994). CNTF induces differentiation of autonomic
neurons (Ernsberger et al., 1989). IL-6 and IL-11 promote neuronal
differentiation of pheochromocytoma and hippocampal precursors,
respectively (Satoh et al., 1988; Mehler et al., 1993). Stimulation of
gp130 also induces differentiation of astrocytes (Johe et al., 1996;
Bonni et al., 1997; McKay, 1997). Mice deficient for either CNTF or LIF
were born normally (Stewart et al., 1992; Escary et al., 1993; Masu et
al., 1993), showing no developmental abnormalities in the nervous
system, but exhibited mild loss of motor neurons in the adulthood (Masu
et al., 1993). Crossing these two lines accelerated motor neuron
degeneration, but the defect was still moderate (Sendtner et al.,
1996). In contrast, CNTF receptor (CNTFR) knock-outs showed
neonatal lethality and significant reduction in the number of motor
neurons (DeChiara et al., 1995). A similar neurological defect was
observed in LIFR-deficient mice (Li et al., 1995), suggesting the
presence of a cytokine, other than CNTF, which binds to CNTFR and
signals through an LIFR-gp130 complex. LIFR-deficient mice exhibited
astrocyte loss as well (Ware et al., 1995; Koblar et al., 1998).
Although mitotic oligodendrocytes were moderately reduced in the
postnatal optic nerve of CNTF-deficient mice, astrocytes looked normal
(Barres et al., 1996). It is thus of much interest to analyze
neurological defects in gp130 knock-out mice in which all the signals
from gp130/gp130, gp130/LIFR, and gp130/OSMR dimers are lost. The
present study has been done for this purpose.
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MATERIALS AND METHODS |
Animals. The effect of gp130 deficiency on the
nervous system has not been extensively examined, partly because the
gp130 knock-out mice on which we reported previously were on the
genetic background of the mixture of 129 and C57BL/6 and died during
development (Yoshida et al., 1996, 1998). In the present study, gp130
knock-out mice on the genetic background of ICR were used. On this
genetic background, some gp130 null mice survive through the late
stages of development to term at an incidence of 9% in total live
newborns from gp130 +/ intercrossings (Kawasaki et al., 1997). Even
in this case, the live newborns die shortly after birth, as observed previously with LIFR- and CNTFR-deficient mice. Mice were treated according to the guidelines of the Tokyo Medical and Dental University Animal Committee.
Cell culture. Neuroepithelial cells were prepared and
cultured as described previously (Johe et al., 1996). In brief,
telencephalons from embryonic day 14.5 (E14.5) mice were
triturated in HBSS by mild and frequent pipetting with 1 ml pipet tip
(Gilson, Middleton, WI). Dissociated cells were cultured for
4 d in N2-supplemented DMEM-F-12 medium containing 10 ng/ml basic
FGF (bFGF) (R & D Systems, Minneapolis, MN)
(N2-DMEM-F-12-bFGF) on a 10 cm dish that had been precoated with
poly-L-ornithine (Sigma, St. Louis, MO) and fibronectin
(Life Technologies, Gaithersburg, MD). Telecephalon-derived cells were plated in one dish with 6 ml of medium. Cells were then
detached in HBSS and replated on chamber slides (Nunc, Naperville, IL)
precoated as above at a density of 8 × 104
cells per well (0.3 ml each, cultured for 3 d).
N2-DMEM-F-12-bFGF medium supplemented with various cytokines were
used for the cell culture.
Immunoblotting. Cells stimulated with either a combination
of IL-6 (100 ng/ml) and soluble IL-6 receptor (sIL-6R) (200 ng/ml) or LIF (100 ng/ml; Genzyme, Boston, MA) were solubilized with NP-40 lysis buffer [0.5% NP-40, 10 mM Tris-Cl, pH 7.4, 150 mM NaCl, 3 mM pAPMSF (Wako Chemicals,
Osaka, Japan), 5 mg/ml aprotinine (Sigma), 2 mM sodium
orthovanadate (Wako Chemicals), and 5 mM EDTA]. Lysates
were immunoprecipitated with anti-gp130 antibody (Santa Cruz
Biotechnology, Santa Cruz, CA) or anti-signal transducer and activator
of transcription (STAT) 3 antibody (kindly provided by Dr. S. Akira, Research Institute for Microbial Disease, Osaka University,
Suita, Japan). Precipitates and, in some cases, cell lysates
were subjected to SDS-PAGE and subsequent immunoblotting with
antibodies to phospho-tyrosine (4G10; Upstate Biotechnology, Lake
Placid, NY), LIFR (Santa Cruz Biotechnology), or STAT3 (Transduction Laboratories, Lexington, KY). Detection was done with an ECL system (Amersham, Arlington Heights, IL).
Histology. Mouse embryos were fixed with 4%
paraformaldehyde in PBS and embedded in paraffin according to
conventional procedures. Serial paraffin sections (7 µm) prepared
with an automated Leica (Nussloch, Germany) rotation microtome were
mounted on glass slides and subjected to Nissl staining. Neurons within
the facial nucleus, the nucleus ambiguus, lumbar motor column (L1-L6),
and L5 dorsal root ganglion (DRG) were counted as described previously
(Li et al., 1995).
Immunofluorescent staining. Cryosections (8 µm; Leica)
prepared from E18.5 brain and cells cultured on chamber slides were fixed with 4% paraformaldehyde in PBS and stained with anti-glial fibrillary acidic protein (GFAP) antibody (Dako, High Wycombe, UK) and rhodamine-conjugated second antibody (Chemicon, Temecula, CA).
For the cultured cells, bisbenzimide H33258 fluorochrome trihydrochloride (Nakaraitesque, Kyoto, Japan) was used to stain nuclei.
Neuron survival assay. T11-L3 DRGs were dissected from each
E18.5 mouse and chopped briefly with a pair of 27G needles in DMEM. Chopped DRGs from each individual mouse were pooled in one well of a 96-well round-bottom plate and resuspended with 150 µl of
dissociation buffer (DMEM containing 0.025% trypsin, 0.01% DNase, and
10 mM HEPES, pH 7.5). Plates were incubated at 37°C in a
humidified chamber and occasionally tapped to suspend DRG fragments in
every 5 min. After 10-15 min, 50 µl of FCS was added to each well to
stop trypsinization. DRG cells were gently suspended with 1 ml pipet
tip (Gilson) and passed through #300 nylon mesh to remove debris and
aggregates. Cells were plated in duplicates in flat-bottom 96-well
Biocoat poly-D-lysine-mouse laminin plates (Becton
Dickinson, Cockeysville, MD) at a final density of 200 cells per well
in 200 µl of DMEM-F-12 containing 10% FCS. The following factors
were used: 1 µg/ml IL-6, 1 µg/ml sIL-6R, 300 ng/ml OSM (Peprotech,
Rocky Hill, NJ), 300 ng/ml LIF (Genzyme), 300 ng/ml CNTF (Genzyme), and
100 ng/ml NGF (Toyobo, Tokyo, Japan). Cells were incubated for 20 hr,
and large bright cells observed under phase-contrast microscopy were counted.
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RESULTS |
Impairment of astrocyte differentiation in the absence of
gp130 signaling
Neuroepithelial cells from E14.5 fetal telencephalon are
considered to contain neuroglial stem cells and have been shown to differentiate into astrocytes when cultured with LIF and CNTF (Johe et
al., 1996; Bonni et al., 1997; McKay, 1997). To examine the effect of
gp130 deficiency on astrocyte differentiation, we cultured
neuroepithelial cells from the gp130 knock-out mice. In these cells,
gp130 signaling is completely missing. As shown in Figure
1A, no tyrosine
phosphorylation of gp130 or STAT3 was observed in gp130 /
neuroepithelial cells stimulated with either LIF or a combination of
IL-6 and sIL-6R, unlike in the case of the wild-type control. In
LIF-stimulated normal control cells, tyrosine phosphorylation of LIFR
was also observed, which was completely missing in gp130 /
cells.
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Figure 1.
Impairment of astrocyte induction in
neuroepithelial cells by the lack of gp130. A, Absence
of gp130 signalings in gp130-deficient cells. Neuroepithelial cells
from E14.5 gp130 +/+ and gp130 / mice were stimulated with either
IL-6 plus sIL-6R or LIF. NP-40 lysates were subjected to
immunoprecipitation and subsequent immunoblotting with the antibodies
indicated, except for the middle panel in which the
lysates were directly analyzed by immunoblotting. B,
Loss of astrocyte induction in gp130-deficient cells in
vitro. Neuroepithelial cells from E14.5 gp130 +/+
(a-d) or gp130 / (e-h) mice were
cultured as described in Materials and Methods with medium alone
(a, e), or IL-6 plus sIL-6R
(b, f), LIF (c,
g), or CNTF (d, h) and
stained for GFAP by specific antibody. GFAP-positive cells and nuclei
are shown in red and blue, respectively,
by fluorescent microscopy.
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E14.5 neuroepithelial cells were then examined for their potential to
differentiate into astrocytes in the presence of gp130-stimulating cytokines. Astrocytes positive for their marker protein GFAP were definitely induced in the normal control cell cultures containing IL-6
plus sIL-6R, LIF, or CNTF (Fig. 1B, b-d).
In marked contrast, no GFAP-positive astrocyte was observed under the
same culture conditions when cells were derived from gp130 /
telencephalon (Fig. 1B, f-h). No cells
with glial morphology are found in the cultures of gp130-deficient
cells (data not shown), suggesting that gp130 signaling is important
for the induction of not only GFAP expression but also glial morphology.
Based on these results obtained in vitro, we wanted to know
whether GFAP-positive astrocytes develop in vivo in the
absence of gp130 signaling. When analyzed by Northern blotting, the
amount of GFAP mRNA in E18.5 gp130 / brain was dramatically reduced to a nearly negligible level (Fig.
2A). GFAP mRNA
expression in gp130 +/ brain showed some reduction.
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Figure 2.
Impairment of GFAP expression in gp130-deficient
brain. A, Loss of GFAP transcripts in gp130-deficient
brain. RNA from E18.5 gp130 +/+, +/, and / brain was analyzed by
Northern blotting with a GFAP-specific probe. B,
Reduction of GFAP-positive cells in gp130-deficient brain. Cryosections
from E18.5 gp130 +/+ and gp130 / brain were stained with
GFAP-specific antibody and rhodamine-conjugated second antibody.
Asterisks indicate fimbria. The dotted
outlines represent the molecular layer of dentate gyrus. No
detectable staining was observed when the first antibody was omitted
during the procedures (data not shown).
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To further demonstrate impairment of astrocyte development in
gp130-deficient mice, cryosections from the gp130 / E18.5 brain
were stained with anti-GFAP antibody. As shown in Figure 2B, the intensity of GFAP immunoreactivity and the
positively stained area were dramatically reduced in gp130-deficient
mice in, for instance, the fimbria and the molecular layer of dentate gyrus. Nevertheless, GFAP dull-positive cells were detected, in particular, in the fimbria of the hippocampus, suggesting that gp130-independent pathways exist that may partly contribute to the
development of GFAP-positive astrocytes.
Neuronal defects in gp130-deficient mice
gp130-stimulating cytokines are known to support survival of
cultured neurons (Ernsberger et al., 1989; Martinou et al., 1992; Horton et al., 1998). From the viewpoint of the survival effect of
gp130 signaling, we first examined responsiveness of DRG neurons prepared from gp130 +/+, +/, and / E18.5 mice to various
cytokines in cultures. Without cytokines, most DRG neurons were dead
after 20 hr of culture, and only 10% remained alive (Fig.
3A). Neurons from gp130 +/+
and +/ DRG could be kept alive when cultured with IL-6 plus sIL-6R,
OSM, LIF, CNTF, or NGF. In contrast, gp130 / neurons did not show
any survival response to these cytokines, except for NGF, which does
not use gp130 for signal transduction.
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Figure 3.
Neuronal defects in gp130-deficient mice.
A, Complete loss of survival response of DRG neurons to
gp130 stimulation. DRG neurons from E18.5 mice with the indicated
genotype were cultured for 20 hr with gp130-stimulating cytokines, as
well as NGF. Live neurons were counted under phase-contrast microscopy.
B, Reduction of neuron numbers in gp130-deficient mice.
Histological sections prepared from E18.5 mice with the indicated
genotype were used for counting neurons in L5 DRG
(p < 0.05; t test), facial
nucleus (FN) (p < 0.05), nucleus ambiguus (NA), and L1-L6 spinal motor
column (SMC) (p < 0.005).
Each column represents mean ± SD of the data from
three individual mice, except for gp130 +/ nucleus ambiguus in which
the mean ± SD fluctuation of the data from two mice was
indicated. C, Histological view of spinal motor neurons.
Representative sections from gp130 +/+ (a) and
gp130 / (b) spinal ventral horn are
shown.
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Based on the above finding, the number of neurons in the L5 DRG from
E18.5 mice was counted in paraffin serial sections. As shown in Figure
3B (left panel), the number of DRG neurons
were significantly smaller in gp130 / mice than in the wild-type controls. There was, however, no significant difference in the number
of E14.5 DRG neurons in gp130 +/+ and gp130 / mice (data not
shown). The second panel in Figure 3B shows
considerable reduction in the number of motor neurons in the facial
nucleus at E18.5. An ~40% reduction in the number of motor neurons
in nucleus ambiguus in E18.5 gp130 / mice was observed (Fig.
3B, third panel). The number of spinal
motor neurons in L1-L6 spinal segments of gp130 / mice was also
significantly reduced on E18.5 (Fig. 3B, fourth panel). When counted on E14.5, the number of motor neurons
in the same segments (i.e., L1-L6) of the spinal cord was not affected by the lack of gp130 (gp130 +/+, 3838 ± 95; gp130 /,
3780 ± 540), as in the case of DRG sensory neurons. Figure
3C shows representative histological sections of the spinal
motor column in E18.5 gp130 +/+ and / mice. In the gp130-deficient
mice, a reduction in the number of intact motor neurons and atrophy of
the remaining neurons are obvious.
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DISCUSSION |
Considering that gp130 is required for signal transduction of all
the IL-6 family of cytokines and that these cytokines signal through
either gp130/gp130 homodimers, gp130/LIFR heterodimers, or gp130/OSMR
heterodimers (Taga and Kishimoto, 1997), neurological phenotype of
gp130-deficient mice was expected to be more severe than that of
LIFR-deficient mice (Li et al., 1995; Ware et al., 1995; Koblar
et al., 1998), because the latter type of mice theoretically lack the
signals of LIF, CNTF, and CT-1, as well as a part of OSM signals, among
the six gp130-stimulating cytokines. However, by comparing the results
from our present study on gp130 knock-outs and those from others on
mice deficient for LIFR (Li et al., 1995) or CNTFR (DeChiara et al.,
1995), it appears that motor neurons are similarly affected in these
three lines of mice. Because the extent of cell death of motor neurons
in gp130 null mice is not higher than that observed in LIFR null mice
(Li et al., 1995), it is suggested that cytokines that signal
through the gp130/LIFR heterodimer are important for the maintenance of
motor neurons and that compensation through gp130/gp130 homodimers
is only minor in LIFR mutant mice.
Similar discussion can be made regarding astrocyte differentiation. In
the gp130-deficient brain, astrocyte differentiation was dramatically
impaired. An almost comparable phenotype was observed in LIFR-deficient
mice (Ware et al., 1995; Koblar et al., 1998). Among the six
known IL-6 type cytokines, those signaling through gp130/LIFR
heterodimers seem to be important for astrocyte differentiation as is
described above for motor neuron survival. In fetal neuroepithelial
cell cultures, GFAP expression is completely absent when gp130 (our
present study) or downstream signaling (Bonni et al., 1997) is
impaired. In the gp130 / mice in vivo, GFAP expression
in the hippocampus is significantly reduced but not null. This suggests
that other minor mechanisms may exist that can support astrocyte
differentiation in vivo. A candidate for such a mechanism is
bone morphogenetic protein (BMP)-induced astrocyte differentiation.
When gp130 / neuroepithelial cells were cultured for 6 d with
BMP2 (80 ng/ml), we observed GFAP-positive cells with astrocyte
morphology, although the intensity of GFAP expression looked dull and
the number of such cells was small (K. Nakashima, M. Yanagisawa, and T. Taga, unpublished data).
Mice lacking CNTFR were also reported to exhibit significant loss of
motor neurons as has been observed in gp130 null mice in the present
study. They, however, did not show detectable loss of DRG neurons
(DeChiara et al., 1995), unlike in the case of the gp130 nulls. It will
be interesting to examine whether DRG neurons are affected in mice
deficient for LIFR. As we have shown in this study, DRG neurons are
significantly reduced by ~20% in gp130 null mice. The obvious
responsiveness of DRG sensory neurons from gp130 / mice to factors
such as NGF could explain why 80% of them can be maintained in the
absence of gp130. There have been several reports showing sensory
neuron deficits in the DRG of mice lacking, for instance, NGF, TrkA,
TrkB, GDNF, and BDNF (Snider, 1994). Signals regulated by these factors
and receptors may compensate for the lack of those regulated by gp130
to support survival of DRG sensory neurons.
Among the three gp130-associating Janus kinase (JAK) family
kinases (JAK1, JAK2, and TYK2) (Narazaki et al., 1994; Taga and Kishimoto, 1997), JAK1 has been suggested to play a primarily important
role (Guschin et al., 1995). Consistent with this suggestion, it
was reported recently that JAK1 deficiency resulted in significant loss
of DRG neuron numbers and almost complete loss of responsiveness of DRG
neurons to gp130-stimulating cytokines (Rodig et al., 1998). It should
be noted, however, that the number of DRG neurons in JAK1-deficient
mice appears more reduced than that in gp130 null mice. This suggests
that JAK1 may also be involved in signal transduction of factors
besides the IL-6 type cytokines.
As for motor neurons, degeneration in the absence of gp130 in
vivo was dramatic (by 40%) (Fig. 3B). The higher loss
of motor neurons compared with DRG sensory neurons suggests that fewer back-up mediators for motor neurons exist in gp130 / mice. In this
context, it should be noted that primarily affected neurons at the
immediate postnatal stage in mice deficient for CNTFR or LIFR are motor
neurons (DeChiara et al., 1995; Li et al., 1995) and that
CNTF-deficient adult mice exhibit loss of motor neurons but not other
neurons (Masu et al., 1993). The findings that motor neurons are more
affected than sensory neurons in gp130 / mice could be of relevance
to the understanding of motor neuron diseases. In the case of
amyotrophic lateral sclerosis, loss of sensory neurons has been
observed, which is, however, much lower than the loss of motor neurons
and does not lead to severe clinical symptoms (Dyck et al., 1975; Jamal
et al., 1985). It will be interesting to know whether gp130-dependent
signaling pathways are disturbed in such patients with motor neuron diseases.
Various neuropoietic and neurotrophic factors are known to support
neuronal differentiation, innervation, and maintenance during
development. Preference of such factors required by a neuronal lineage
of cells may change in the course of development. The present study has
shown that gp130 deficiency did not result in detectable neuronal
defect on E14.5 but did lead to significant loss of both motor and
sensory neurons on E18.5. This suggests that gp130-stimulating
cytokines may not function in neuronal differentiation during earlier
developmental stages but may have an important role in the maintenance
of already differentiated neurons. A supportive evidence for this idea
is that survival response of trigeminal ganglion neurons to
gp130-stimulating cytokines is almost negligible on day 14 of
development but is dramatically increased on day 19 to the extent
almost comparable with that observed with NGF (Horton et al., 1998), as
has been demonstrated by our experiments in Figure 3A.
Another supportive report is that transgenic mice with forced
expression of IL-6 and IL-6R show constitutive activation of gp130 and
exhibit accelerated motor nerve regeneration after surgical injury of
hypoglossal nerve, although these mice have a developmentally normal
number of hypoglossal motor neurons (Hirota et al., 1996). LIF and CNTF have been suggested to function as a cholinergic differentiation factor
that induces a transmitter switch from noradrenergic phenotype to a
cholinergic one in cultured sympathetic neurons (Yamamori et al., 1989;
Patterson, 1994). However, mice lacking CNTF, LIF, or both did not show
detectable developmental abnormalities in cholinergic properties of
parasympathetic neurons, at least in the sweat glands and periosteum
(Francis et al., 1997), whereas injury response of differentiated
sympathetic neurons was affected at least in LIF-deficient mice (Rao et
al., 1993).
It has been suggested that there exists a common neural precursor that
can differentiate into both neurons and astrocytes (Turner and Cepko,
1987; Kilpatrick and Bartlett, 1995; Bonni et al., 1997; McKay, 1997).
In gp130 knock-out mice, both of these neural cell populations at the
late developmental stage were affected. However, our results suggest
that the deficits observed in motor neurons and astrocytes are probably
not a result of actions through gp130 at the stem cell level, because
E14.5 gp130 null mice have normal numbers of motor neurons and sensory neurons.
In the present study, we have focused on the neurological defects in
gp130-deficient mice at the late stage of development. gp130-deficient
mice die during development and shortly after birth. Even the live-born
gp130 / mice on the ICR genetic background die shortly after birth
without feeding. It will be interesting to examine relevance between
the neurological abnormalities found in E18.5 gp130 / mice and
neonatal death of this line of mice. With the use of these mice,
physiological function of gp130 after birth could not be examined.
Therefore, techniques have been developed to inactivate gp130 in mice
by application of the Cre/loxP-mediated recombination system. By
these techniques, Betz et al. (1998) were able to show that postnatal
Schwann cells depend on gp130 for their integrity and the maintenance
of myelinated and unmyelinated peripheral nerve fibers. With the
improvement of appropriate techniques to delete gp130 specifically in
postnatal motor neurons and astrocytes, it will be possible to examine
whether gp130-dependent signaling pathways are also necessary for the
maintenance of adult motor neurons and astrocytes and whether the
dependence on the gp130 signals increase or decrease during postnatal development.
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FOOTNOTES |
Received Jan. 13, 1999; revised April 14, 1999; accepted April 20, 1999.
This work has been supported by a grant-in-aid from the Ministry of
Education, Science, and Culture, Human Frontier Science Program, Cell
Science Research Foundation, Kowa Life Science foundation, and Cell
Fate Modulation Research Unit of Medical Research Institute of Tokyo
Medical and Dental University. We thank Dr. Hiroshi Kiyama for helpful
comments and discussions and Dr. Kiyoshi Yasukawa for generously
providing us with sIL-6R. We are very grateful to Yuko Nakamura for her
excellent secretarial assistance. We also thank Kyoko Saito for
technical help. Preparation of histological samples was done with
generous help and suggestions of Tayoko Tajima, Hiromi Tanizawa, Dr.
Toshihiro Kuroiwa, and Dr. Riki Okeda.
Correspondence should be addressed to Dr. Tetsuya Taga, Department of
Molecular Cell Biology, Medical Research Institute, Tokyo Medical and
Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku Tokyo 101-0062, Japan.
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REFERENCES |
-
Barres BA,
Burne JF,
Holtmann B,
Thoenen H,
Sendtner M,
Raff MC
(1996)
Ciliary neurotrophic factor enhances the rate of oligodendrocyte generation.
Mol Cell Neurosci
8:146-156.
-
Betz UAK,
Bloch W,
van den Broeck M,
Yoshida K,
Taga T,
Zinkernagel R,
Kishimoto T,
Addicks K,
Rajewsky K,
Müller WJ
(1998)
Postnatally induced inactivation of gp130 in mice results in neurological, cardiac, hematopoietic, immunological, hepatic and pulmonary defects.
J Exp Med
188:1955-1965[Abstract/Free Full Text].
-
Bonni A,
Sun Y,
Nadal-Vicens M,
Bhatt A,
Frank DA,
Rozovsky I,
Stahl N,
Yancopoulos GD,
Greenberg ME
(1997)
Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway.
Science
278:477-483[Abstract/Free Full Text].
-
Davis S,
Aldrich TH,
Stahl N,
Pan L,
Taga T,
Kishimoto T,
Ip NY,
Yancopoulos GD
(1993)
LIFR
 and gp130 as heterodimerizing signal transducers of the tripartite CNTF receptor.
Science
260:1805-1808[Abstract/Free Full Text]. -
DeChiara TM,
Vejsada R,
Poueymirou WT,
Acheson A,
McClain J,
Pan L,
Stahl N,
Ip NY,
Kato A,
Yancopoulos GD
(1995)
Mice lacking the CNTF receptor, unlike mice lacking CNTF, exhibit profound motor neuron deficits at birth.
Cell
83:313-322[Web of Science][Medline].
-
Dyck PJ,
Stevens JC,
Mulder DW,
Espinosa RE
(1975)
Frequency of nerve fiber degeneration of peripheral motor and sensory neurons in amyotrophic lateral sclerosis: morphometry of deep and superficial peroneal nerves.
Neurology
25:781-787[Abstract/Free Full Text].
-
Ernsberger U,
Sendtner M,
Rohrer H
(1989)
Proliferation and differentiation of embryonic chick sympathetic neurons: effects of ciliary neurotrophic factor.
Neuron
2:1275-1284[Web of Science][Medline].
-
Escary JL,
Perreau J,
Duménil D,
Ezine S,
Brulet P
(1993)
Leukemia inhibitory factor is necessary for maintenance of haematopoietic stem cells and thymocyte stimulation.
Nature
363:361-364[Medline].
-
Francis NJ,
Asmus SE,
Landis SC
(1997)
CNTF and LIF are not required for the target-directed acquisition of cholinergic and peptidergic properties by sympathetic neurons in vivo.
Dev Biol
182:76-87[Web of Science][Medline].
-
Guschin D,
Rogers N,
Briscoe J,
Witthuhn B,
Watling D,
Hom F,
Pellegrini S,
Yasukawa K,
Heinrich P,
Stark GR,
Ihle JN,
Kerr IM
(1995)
A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6.
EMBO J
14:1421-1429[Web of Science][Medline].
-
Hirota H,
Kiyama H,
Kishimoto T,
Taga T
(1996)
Accelerated nerve regeneration in mice by upregulated expression of interleukin (IL) 6 and IL-6 receptor after trauma.
J Exp Med
183:2627-2634[Abstract/Free Full Text].
-
Horton AR,
Bartlett PF,
Pennica D,
Davies M
(1998)
Cytokines promote the survival of mouse cranial sensory neurons at different developmental stages.
Eur J Neurosci
10:673-679[Web of Science][Medline].
-
Jamal GA,
Wei AI,
Hansen S,
Ballantyne JP
(1985)
Sensory involvement in motor neuron disease: further evidence from automated thermal threshold determination.
J Neurol Neurosurg Psychiatry
48:906-910[Abstract/Free Full Text].
-
Johe KK,
Hazel TG,
Muller T,
Dugich-Djordjevic MM,
McKay RDG
(1996)
Single factors direct the differentiation of stem cells from the fetal and adult central nervous system.
Genes Dev
10:3129-3140[Abstract/Free Full Text].
-
Kawasaki K,
Gao YH,
Yokose S,
Kaji Y,
Nakamura T,
Suda T,
Yoshida K,
Taga T,
Kishimoto T,
Kataoka H,
Yuasa T,
Norimatsu H,
Yamaguchi A
(1997)
Osteoclasts are present in gp130-deficient mice.
Endocrinology
138:4959-4965[Abstract/Free Full Text].
-
Kilpatrick TJ,
Bartlett PF
(1995)
Cloned multipotential precursors from the mouse cerebrum require FGF-2, whereas glial restricted precursors are stimulated with either FGF-2 or EGF.
J Neurosci
15:3653-3661[Abstract].
-
Kishimoto T,
Taga T,
Akira S
(1994)
Cytokine signal transduction.
Cell
76:253-262[Web of Science][Medline].
-
Koblar SA,
Turnley AM,
Classon BJ,
Reid KL,
Ware CB,
Cheema SS,
Murphy M,
Bartlett PF
(1998)
Neural precursor differentiation into astrocytes requires signaling through the leukemia inhibitory factor receptor.
Proc Natl Acad Sci USA
95:3178-3181[Abstract/Free Full Text].
-
Kopf M,
Baumann H,
Freer G,
Freudenberg M,
Lamers M,
Kishimoto T,
Zinkernagel R,
Bluethmann H,
Kàhler G
(1994)
Impaired immune and acute-phase responses in interleukin-6-deficient mice.
Nature
368:339-342[Medline].
-
Li M,
Sendtner M,
Smith A
(1995)
Essential function of LIF receptor in moter neurons.
Nature
378:724-727[Medline].
-
Martinou JC,
Martinou I,
Kato AC
(1992)
Cholinergic differentiation factor (CDF/LIF) promotes survival of isolated rat embryonic motoneurons in vitro.
Neuron
8:737-744[Web of Science][Medline].
-
Masu Y,
Wolf E,
Holtmann B,
Sendtner M,
Brem G,
Thoenen H
(1993)
Disruption of the CNTF gene results in motor neuron degeneration.
Nature
365:27-32[Medline].
-
McKay R
(1997)
Stem cells in the central nervous system.
Science
276:66-71[Abstract/Free Full Text].
-
Mehler MF,
Rozental R,
Dougherty M,
Spray DC,
Kessler JA
(1993)
Cytokine regulation of neuronal differentiation of hippocampal progenitor cells.
Nature
362:62-65[Medline].
-
Murakami M,
Hibi M,
Nakagawa N,
Nakagawa T,
Yasukawa K,
Yamanishi K,
Taga T,
Kishimoto T
(1993)
IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase.
Science
260:1808-1810[Abstract/Free Full Text].
-
Narazaki M,
Witthuhn BA,
Yoshida K,
Silvennoinen O,
Yasukawa K,
Ihle JN,
Kishimoto T,
Taga T
(1994)
Activation of JAK2 kinase mediated by the interleukin 6 signal transducer gp130.
Proc Natl Acad Sci USA
91:2285-2289[Abstract/Free Full Text].
-
Patterson PH
(1994)
Leukemia inhibitory factor, a cytokine at the interface between neurobiology and immunology.
Proc Natl Acad Sci USA
91:7833-7835[Free Full Text].
-
Rao MS,
Sun Y,
Escary JL,
Perreau J,
Tresser S,
Patterson PH,
Zigmond RE,
Brulet P,
Landis SC
(1993)
Leukemia inhibitory factor mediates an injury response but not a target-directed developmental transmitter switch in sympathetic neurons.
Neuron
11:1175-1185[Web of Science][Medline].
-
Rodig SJ,
Meraz MA,
White JM,
Lampe PA,
Riley JK,
Arther CD,
King KL,
Sheehan KCF,
Yin L,
Pennica D,
Johnson Jr EM,
Schreiber RD
(1998)
Disruption of the JAK1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses.
Cell
93:373-383[Web of Science][Medline].
-
Satoh T,
Nakamura S,
Taga T,
Matsuda T,
Hirano T,
Kishimoto T,
Kaziro Y
(1988)
Induction of neuronal differentiation in PC12 cells by B cell stimulatory factor 2/Interleukin 6.
Mol Cell Biol
8:3546-3549[Abstract/Free Full Text].
-
Sendtner M,
Gotz R,
Holtmann B,
Escary JL,
Masu Y,
Carroll P,
Wolf E,
Brem G,
Brulet P,
Thoenen H
(1996)
Cryptic physiological trophic support of motoneurons by LIF revealed by double gene targeting of CNTF and LIF.
Curr Biol
6:686-694[Web of Science][Medline].
-
Snider WD
(1994)
Functions of the neurotrophins during nervous development: what the knockouts are teaching us.
Cell
77:627-638[Web of Science][Medline].
-
Stahl N,
Yancopoulos GD
(1994)
The tripartite CNTF receptor complex: activation and signaling involves components shared with other cytokines.
J Neurobiol
25:1454-1466[Web of Science][Medline].
-
Stewart CL,
Kaspar P,
Brunet LJ,
Bhatt H,
Gadi I,
Kàntgen F,
Abbondanzo JS
(1992)
Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor.
Nature
359:76-79[Medline].
-
Taga T
(1996)
gp130, a shared signal transducing receptor component for hematopoietic and neuropoietic cytokines.
J Neurochem
67:1-10[Web of Science][Medline].
-
Taga T,
Kishimoto T
(1997)
gp130 and the interleukin-6 family of cytokines.
Annu Rev Immuol
15:797-819[Web of Science][Medline].
-
Taga T,
Hibi M,
Hirata Y,
Yamasaki K,
Yasukawa K,
Matsuda T,
Hirano T,
Kishimoto T
(1989)
Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130.
Cell
58:573-581[Web of Science][Medline].
-
Taga T,
Narazaki M,
Yasukawa K,
Saito T,
Miki D,
Hamaguchi M,
Davis S,
Shoyab M,
Yancopoulos GD,
Kishimoto T
(1992)
Functional inhibition of hematopoietic and neurotrophic cytokines by blocking the interleukin 6 signal transducer gp130.
Proc Natl Acad Sci USA
89:10998-11001[Abstract/Free Full Text].
-
Turner DL,
Cepko CL
(1987)
A common progenitor for neurons and glia persists in rat retina late in development.
Nature
328:131-136[Medline].
-
Ware CB,
Horowitz MC,
Renshaw BR,
Hunt JS,
Liggitt D,
Koblar SA,
Gliniak BC,
McKenna HJ,
Papayannopoulou T,
Thoma B,
Cheng L,
Donovan PJ,
Peschon JJ,
Bartlett PF,
Willis CR,
Wright BD,
Carpenter MK,
Davison BL,
Gearing DP
(1995)
Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death.
Development
121:1283-1299[Abstract].
-
Yamamori T,
Fukada K,
Aebersold R,
Korsching S,
Fann MJ,
Patterson PH
(1989)
The cholinergic neuronal differentiation factor from heart cells is identical to leukemia inhibitory factor.
Science
246:1412-1416[Abstract/Free Full Text].
-
Yoshida K,
Taga T,
Saito M,
Suematsu S,
Kumanogoh A,
Tanaka T,
Fujiwara H,
Hirata M,
Yamagami T,
Nakahata T,
Hirabayashi T,
Yoneda Y,
Tanaka K,
Wang WZ,
Mori C,
Shiota K,
Yoshida N,
Kishimoto T
(1996)
Targeted disruption of gp130, a common signal transducer for IL-6-family of cytokines, leads to myocardial and hematological disorders.
Proc Natl Acad Sci USA
93:407-411[Abstract/Free Full Text].
-
Yoshida K,
Taga T,
Saito M,
Kumanogoh A,
Tanaka T,
Ozono K,
Nakayama M,
Nakahata T,
Yoshida N,
Kishimoto T
(1998)
Myocardial, hematological, and placental disorders caused by targeted disruption of gp130, a common signal transducer for IL-6 family of cytokines.
In: Contemporary immunology: cytokine knockouts (Durum SK,
Muegge K,
eds), pp 259-286. Totowa, NJ: Humana.
Copyright © 1999 Society for Neuroscience 0270-6474/99/19135429-06$05.00/0
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|
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|
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|
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|
|
|
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|
|
|
|
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|
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[PDF]
|
|
|
|
|
|
|
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[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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[Full Text]
[PDF]
|
|
|
|
|
|
|
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[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
|
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|
|
|
|
|
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[PDF]
|
|
|
|
|
|
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279(5):
3852 - 3861.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
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5723 - 5731.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
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[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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J. Neurosci.,
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10333 - 10345.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Hatta, K. Moriyama, K. Nakashima, T. Taga, and H. Otani
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J. Neurosci.,
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22(13):
5516 - 5524.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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Neuroscientist,
June 1, 2002;
8(3):
268 - 275.
[Abstract]
[PDF]
|
|
|
|
|
|
|
A. K. Kamaraju, C. Bertolotto, J. Chebath, and M. Revel
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J. Biol. Chem.,
April 19, 2002;
277(17):
15132 - 15141.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Shimazaki, T. Shingo, and S. Weiss
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J. Neurosci.,
October 1, 2001;
21(19):
7642 - 7653.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Nichols, I. Chambers, T. Taga, and A. Smith
Physiological rationale for responsiveness of mouse embryonic stem cells to gp130 cytokines
Development,
June 15, 2001;
128(12):
2333 - 2339.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Nakashima, T. Takizawa, W. Ochiai, M. Yanagisawa, T. Hisatsune, M. Nakafuku, K. Miyazono, T. Kishimoto, R. Kageyama, and T. Taga
BMP2-mediated alteration in the developmental pathway of fetal mouse brain cells from neurogenesis to astrocytogenesis
PNAS,
April 25, 2001;
(2001)
101109698.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
H. Mi, H. Haeberle, and B. A. Barres
Induction of Astrocyte Differentiation by Endothelial Cells
J. Neurosci.,
March 1, 2001;
21(5):
1538 - 1547.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. W. Oppenheim, S. Wiese, D. Prevette, M. Armanini, S. Wang, L. J. Houenou, B. Holtmann, R. Gotz, D. Pennica, and M. Sendtner
Cardiotrophin-1, a Muscle-Derived Cytokine, Is Required for the Survival of Subpopulations of Developing Motoneurons
J. Neurosci.,
February 15, 2001;
21(4):
1283 - 1291.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. E. Holmes, S. Mahoney, V. R. King, A. Bacon, N. C. H. Kerr, V. Pachnis, R. Curtis, J. V. Priestley, and D. Wynick
Targeted disruption of the galanin gene reduces the number of sensory neurons and their regenerative capacity
PNAS,
September 29, 2000;
(2000)
210221897.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
C. J. Auernhammer and S. Melmed
Leukemia-Inhibitory Factor--Neuroimmune Modulator of Endocrine Function
Endocr. Rev.,
June 1, 2000;
21(3):
313 - 345.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
Y. Wang, O. Robledo, E. Kinzie, F. Blanchard, C. Richards, A. Miyajima, and H. Baumann
Receptor Subunit-specific Action of Oncostatin M in Hepatic Cells and Its Modulation by Leukemia Inhibitory Factor
J. Biol. Chem.,
August 11, 2000;
275(33):
25273 - 25285.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. A. Jones, J. Conover, and A. J. Symes
Identification of a Novel gp130-responsive Site in the Vasoactive Intestinal Peptide Cytokine Response Element
J. Biol. Chem.,
November 10, 2000;
275(46):
36013 - 36020.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Nakashima, T. Takizawa, W. Ochiai, M. Yanagisawa, T. Hisatsune, M. Nakafuku, K. Miyazono, T. Kishimoto, R. Kageyama, and T. Taga
BMP2-mediated alteration in the developmental pathway of fetal mouse brain cells from neurogenesis to astrocytogenesis
PNAS,
May 8, 2001;
98(10):
5868 - 5873.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. E. Holmes, S. Mahoney, V. R. King, A. Bacon, N. C. H. Kerr, V. Pachnis, R. Curtis, J. V. Priestley, and D. Wynick
Targeted disruption of the galanin gene reduces the number of sensory neurons and their regenerative capacity
PNAS,
October 10, 2000;
97(21):
11563 - 11568.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
U. Schweizer, J. Gunnersen, C. Karch, S. Wiese, B. Holtmann, K. Takeda, S. Akira, and M. Sendtner
Conditional gene ablation of Stat3 reveals differential signaling requirements for survival of motoneurons during development and after nerve injury in the adult
J. Cell Biol.,
January 21, 2002;
156(2):
287 - 298.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
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ABSTRACT
INTRODUCTION
