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with the Secretion of Neuroactive Substances That Stimulate the Release of Luteinizing Hormone-Releasing Hormone1
Division of Neuroscience, Oregon Regional Primate Research Center, Oregon Health Sciences University (Y.J.M., K.B.E., F.R., S.R.O.), Beaverton, Oregon 97006; and the Laboratory of Cell and Molecular Pharmacology, National Institute of Environmental and Health Science (W.C.W.), Research Triangle Park, North Carolina 27709
Address all correspondence and requests for reprints to: Dr. Sergio R. Ojeda, Division of Neuroscience, Oregon Regional Primate Research Center, Oregon Health Sciences University, 505 NW 185th Avenue, Beaverton, Oregon 97006.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(TGF), a member of the epidermal growth factor (EGF)
family, in the developmental regulation of hypothalamic LHRH release.
Although both TGF and EGF stimulate LHRH release, they do not appear
to act directly on LHRH neurons, as no EGF/TGF receptors are
detected on these cells in vivo. Instead, the
stimulatory effect of TGF on LHRH release seems to require a glial
intermediacy. The present study identifies one of the glial molecules
involved in this process. In vitro exposure of purified
hypothalamic astrocytes to TGF or EGF in a defined medium led to
activation of the cyclooxygenase-mediated pathway of arachidonic acid
metabolism, as indicated by an increase in PGE2 release,
but failed to affect lipooxygenase-mediated metabolism, as assessed by
the lack of increase in leukotriene C4 production; addition of TGF-
(T-CM) or EGF-conditioned medium to cultures of LHRH-producing GT1-1
cells stimulated LHRH release. In contrast, direct exposure of GT1-1
cells to the growth factors was ineffective. Incubation of the cells in
medium conditioned by untreated astrocytes (CM) was also ineffective.
Blockade of either EGF receptor signal transduction or cyclooxygenase
activity in the astrocytic cultures prevented both TGF-induced
PGE2 formation in astrocytes and the stimulatory effect of
T-CM on LHRH release. Immunoneutralization of PGE2 actions
or selective removal of the PG from T-CM also prevented T-CM-induced
LHRH release. Addition of exogenous PGE2 restored the
effect. Thus, PGE2 is one of the glial molecules involved
in mediating the stimulatory effect of TGF on LHRH release. The
effectiveness of PGE2 in eliciting LHRH release was,
however, greatly reduced when PG was delivered to GT1-1 cells in
astrocyte-defined medium instead of CM. Thus, astrocytes appear to
produce a yet to be identified substance(s) that facilitates the
stimulatory effect of PGE2 on LHRH output. We postulate
that the ability of TGF to enhance LHRH release depends on the
potentiating interaction of PGE2 with these additional
glial-derived molecules. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In addition to such neurotransmitter-mediated regulation, a body of evidence is beginning to emerge in support of the concept that LHRH neuronal function is also influenced by molecules of astrocytic origin (3, 4) that are able to affect not only the release of LHRH (5), but also the morphological and biochemical differentiation of the LHRH neuronal network (6, 7, 8).
For instance, heat-labile molecules produced by astrocytes have been shown to enhance the neuronal phenotype, induce LHRH release, and promote the proliferation of a LHRH neuronal cell line (7). Other experiments have demonstrated that astrocytes can also produce heat-resistant bioactive substances that are able to stimulate LHRH output. One of these LHRH-releasing substances has been tentatively identified as transforming growth factor-ß1 (TGFß1) (8). The results of these two studies are consistent with the suggestion proposed earlier that the cell-cell regulatory mechanisms used by glial cells to influence LHRH neuronal function involve trophic molecules of a peptidergic nature (3, 4).
An important group of glial regulatory molecules is represented by
growth factors acting via tyrosine kinase receptors, such as basic
fibroblast growth factor (bFGF) (6, 9) and TGF (5, 10). The former
acts directly on LHRH neurons, via activation of specific receptor
molecules, to enhance neuronal differentiation and to promote
processing of the LHRH prohormone, without stimulating release of the
mature decapeptide (6, 9, 11). TGF, on the other hand, is an
effective stimulator of LHRH release (5, 6), but it does not appear to
act directly on LHRH neurons to exert this stimulatory effect (5, 6, 12). Instead, the receptors that recognize TGF have been detected on
astrocytes (6, 13), suggesting that the stimulatory effect of TGF on
LHRH release involves the intermediacy of glial cells (5, 6, 10, 13).
As hypothalamic astrocytes express the genes for both TGF and its
receptor (12, 13) and because they respond to TGF with up-regulation
of its own gene expression (12), we postulated that TGF acts in a
paracrine/autocrine fashion to stimulate the astrocytic production of
bioactive molecules able to enhance LHRH release (5, 12, 13).
The findings that TGF stimulates both LHRH and PGE2
release from median eminence fragments and that this increase in LHRH
release can be suppressed by blocking PG synthesis (5) led to the
suggestion that PGE2 is one of the glial molecules involved
in the astrocyte-dependent regulation of LHRH secretion (4, 5). The
present study provides experimental evidence in support of this
concept. Partial reports of these findings have appeared previously
(14, 15).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cell culture
Astrocytes. Hypothalamic astrocytes were isolated by the
method of McCarthy and de Vellis (16), as previously reported (12).
Briefly, after culturing hypothalamic cell dispersates to confluency
(8–10 days), contaminating cells (neurons and oligodendrocytes) were
removed by shaking the cultures at 250 rpm for 6 h, replacing the
medium, and shaking again for 18 h. The astrocytes were then
seeded in 6-well plates at 800,000 cells/well and grown in DMEM-Ham’s
F-12 medium (1:1, vol/vol) supplemented with 10% calf serum until
reaching 90% confluence (
4 days). At this time, the growth medium
was replaced by an astrocyte-defined medium (ADM; see below), and the
cells were cultured for an additional 48 h before treatment. We
have previously shown that the cultures are more than 95% pure, as
assessed by the number of cells containing the astrocytic marker glial
fibrillary acidic protein (12). ADM consisted of DMEM (lacking
glutamate and phenol red) supplemented with L-glutamine (2
mM), HEPES (15 mM), insulin (5 µg/ml), and
putrescine (100 µM).
GT1-1 cells. These cells were seeded in 24-well plates at 200,000 cells/well and grown in DMEM containing 10% FCS, penicillin (100 U/ml), and streptomycin (100 µg/ml) under an atmosphere of 5% CO2-95% air at 37 C. Upon reaching 50–60% confluence, the medium was replaced with a neuronal defined medium (6) consisting of glutamate-free DMEM supplemented with transferrin (100 µg/ml), putrescine (100 µM), L-glutamine (2 mM), sodium selenite (30 nM), and insulin (5 µg/ml). The cells were used for experiments 24 h later.
Treatments
Astrocytes. In a previous study (12) we reported that both
TGF and epidermal growth factor (EGF) at 50 ng/ml and the phorbol
ester 12-O-tetradecanoyl phorbol-13-acetate (TPA) at 10
ng/ml were highly effective in inducing TGF gene expression in
cultures of hypothalamic astrocytes. We also reported that similar
doses of TGF and EGF stimulate PGE2 release from median
eminence fragments in vitro (5). The same doses were,
therefore, used in the present study to determine whether hypothalamic
astrocytes respond to activation of EGF receptors (EGFR) by TGF or
EGF or to activation of protein kinase C-mediated pathways by TPA with
the release of substances able to stimulate LHRH release. As previous
results implicated PGE2 as one of these bioactive
substances (5), it was used as the end point in culture medium
collected after 4, 8, 16, and 24 h of treatment. Based on the
release profile of the PG, the 16-h interval was selected for
collection of medium conditioned by untreated astrocytes (CM) or by
astrocytes treated with TGF- (T-CM) or EGF (E-CM).
Because 16-h T-CM treatment effectively released LHRH from GT1-1 cells,
experiments were conducted to verify that both the effect of TGF on
PGE2 release and the conditioning effect of the growth
factor on astrocyte culture medium involve activation of EGFR. In these
experiments, astrocytes were simultaneously treated with TGF (50
ng/ml) and tyrphostin RG-50864 (60 µM), a selective
inhibitor of EGFR tyrosine kinase activity (17) (Rhône-Poulenc
Rorer Central Research, Horsham, PA); we previously showed that
treatment of hypothalamic astrocytes with this dose of RG-50864 blocks
the effect of TGF on its own gene expression (12).
Additional experiments were performed to determine whether the
conditioning effect of TGF involves only the formation of products
in the cyclooxygenase pathway of arachidonic acid metabolism or if it
also includes the formation of lipooxygenase metabolites. To examine
this issue, leukotriene C4 (LTC4) and
PGE2 were measured in the culture medium of astrocytes
treated with TGF for 16 h. Other cultures were treated with
TGF plus different doses of indomethacin (Id), a preferential
cyclooxygenase inhibitor, or nordihydroguaiaretic acid (NDGA), a
preferential lipooxygenase inhibitor. In addition to measuring
LTC4 and PGE2, the effectiveness of the
treatments was determined by assessing the ability of the different
media to stimulate LHRH release from GT1-1 cells.
GT1-1 cells. To determine whether T-CM or E-CM was able to
stimulate LHRH release, GT1-1 cells were exposed to CM, E-CM, or T-CM
for 30 min, and the medium was collected for LHRH measurement. A direct
stimulatory effect of TGF and EGF on GT1-1 cells was assessed by
treating GT1-1 cells, cultured in neuronal defined medium, with either
growth factor. As the signal transduction pathway that mediates the
effects of TGF and EGF on cellular function involves activation of
protein kinase C (18, 19), parallel cultures were treated with TPA to
ensure that the cells were responsive to the direct,
nonreceptor-mediated, activation of this pathway.
T-CM from astrocytes in which the cyclooxygenase pathway had been
inhibited by Id failed to stimulate LHRH release, suggesting that the
effect of T-CM requires the presence of cyclooxygenase products. As
TGF induces PGE2 release from hypothalamic astrocytes
(this study), and PGE2 is the major cyclooxygenase product
involved in the control of LHRH release (20), two series of experiments
were carried out to define the role of PGE2 in T-CM-induced
LHRH release. In the first, T-CM was incubated with the highly specific
PGE2 antiserum C510-11/23 (21) for 30 min at room
temperature (10 µl antiserum/ml T-CM) before addition to GT1-1 cells.
Control tubes were incubated with a similar volume of normal rabbit
serum. In the second series, various dilutions of the PGE2
antiserum were added to T-CM and incubated for 1 h at room
temperature, followed by the addition of 300 µl of a 1:1 slurry of
protein A-Sepharose (Sigma Chemical Co., St. Louis, MO) in PBS and
incubation of the mixture for 1 h at room temperature with
constant tipping. Antibody-PGE2-protein A-Sepharose
complexes were then removed by centrifugation at 13,000 x
g for 1 min. The effectiveness of this immunoneutralization
was assessed by measuring PGE2 by RIA. A 1:750 ratio of
antibody to T-CM (vol/vol) effectively removed all measurable
PGE2 from the culture medium. GT1-1 cells were then treated
with this medium, and the ability of exogenous PGE2 to
restore the effect of T-CM on LHRH release was determined by adding a
known amount (2 ng/ml) of PGE2 to the
PGE2-depleted T-CM.
RIAs
PGE2. PGE2 released
by cultured astrocytes was measured as previously described (21). The
tritiated PGE2
([5,6,8,11,14,15-N-3H]PGE2; 171 Ci/mmol) used
in the assay was obtained from DuPont-New England Nuclear (Wilmington,
DE); the PGE2 antiserum (C510-11/23) was a generous gift
from W. B. Campbell (Department of Pharmacology, Medical College of
Wisconsin) and was used at a 1:8,000 dilution. The sensitivity of the
assay was 3.6 pg PGE2/tube.
LHRH. LHRH released by GT1-1 cells into the culture medium was measured as previously reported (22). The assay employs 125I-labeled LHRH and the polyclonal antibody HFU60 (5) at a 1:25,000 dilution. The sensitivity of the assay was 2 pg/tube.
LTC4
An ELISA kit (Neogen Corp., Lexington, KY) was employed to
measure the release of LTC4 from hypothalamic
astrocytes. This assay is based on the competition between the unknown
levels of LTC4 in experimental samples and a
LTC4-horseradish peroxidase conjugate to bind a limiting
amount of LTC4 antibody. The reaction is developed by
measuring the degree of peroxidation of the substrate 3,3',5,5'
tetramethylbenzidine in the presence of hydrogen peroxide.
One-milliliter aliquots of culture medium were acidified with 1
N HCl (150 µl) and applied to C18 Sep-Pak
columns (Waters Corp., Milford, MA) preconditioned by washing with 2 ml
ethanol followed by 2 ml water. Upon application of the acidified
sample, the column was washed with 1 ml water, followed by 1 ml
petroleum ether (Sigma). The eicosanoids were then eluted with 1 ml
formic acid methyl ester (Sigma). After evaporation of the solvent
under a stream of nitrogen at room temperature (30 min), the residue
was dissolved in 200 µl assay buffer (provided by the manufacturer),
and LTC4 was quantitated by ELISA in 50-µl samples. The
concentrations of LTC4 were expressed as picograms per ml.
The sensitivity of the assay was 2 pg/tube.
Statistics
The effect of different treatments was analyzed using a one-way
ANOVA followed by the Student-Newman-Keuls multiple comparison test for
unequal replications.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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requires a glial
intermediacy or EGF failed to affect LHRH release (Fig. 1
, left panel). That the cells were
responsive to activation of one of the intracellular pathways used by
these growth factors was shown by the ability of TPA, an activator of
protein kinase C, to significantly stimulate LHRH release in parallel
cultures. In contrast to their lack of direct response to TGF, GT1-1
cells responded to T-CM or E-CM with a 2-fold increase in LHRH release
compared to that in control cells treated with CM (Fig. 1, right
panel). Medium conditioned by treating the astrocytes with TPA was
also effective, but it did not result in a LHRH response greater than
that caused by TPA alone.
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with increased formation of
PGE2 results in PGE2 release (5), the
ability of TGF and EGF to induce PGE2 release from
hypothalamic astrocytes was examined. Figure 2 shows
that both TGF and EGF stimulate PGE2 production, with
levels of PG increasing almost linearly between 4–24 h of treatment.
TPA was more effective than either growth factor in stimulating
PGE2 release (Fig. 2).
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on
PGE2 release and significantly reduced basal
PGE2 output (Fig. 3, upper left
panel). Moreover, the blocker eliminated the stimulatory effect of
T-CM on LHRH release (Fig. 3, lower left panel). This
inhibition was not due to a direct action of the receptor blocker on
GT1-1 cells, because addition of RG-50854 to the cells failed to alter
basal LHRH release (Fig. 3, open circles, lower left
panel).
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to stimulate PG release upon
blockade of glial EGFR. To verify this assumption, we treated astrocyte
cultures with TGF in the presence of Id, an inhibitor of PG
synthesis and measured both PGE2 levels in the astrocyte
culture medium and the LHRH response to Id-treated T-CM. Figure 3
shows
that Id suppressed both basal and TGF-stimulated PGE2
formation (upper right panel) and eliminated the stimulatory
effect of T-CM on LHRH release (lower right panel). Direct
addition of Id to GT1-1 cells did not affect LHRH release (Fig. 3, open circles, lower right panel).
Products of the lipooxygenase pathway of arachidonic acid
metabolism do not mediate the stimulatory effect of T-CM on LHRH
release
In contrast to the clear-cut elevation in PGE2 levels
observed after 16 h of TGF treatment, levels of
LTC4, the major product of the lipooxygenase pathway (23),
were not increased over control values (Fig. 4, middle panel). Low doses (0.5–1 µM) of NDGA,
a blocker of lipooxygenase activity, affected neither the glial
PGE2 response to TGF nor the increase in LHRH induced by
T-CM (Fig. 4). Higher doses (5 and 10 µM) suppressed the
LHRH response to T-CM (Fig. 4, lower panel), but they also
inhibited the stimulation of glial PGE2 by TGF (Fig. 4, upper panel), without affecting the basal release of
LTC4. Thus, the ability of NDGA to block the effect of T-CM
on LHRH release is due to inhibition of PG synthesis and not to
suppression of lipooxygenase activity.
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). Treatment of T-CM with normal
rabbit serum was ineffective. Basal LHRH release was not altered by the
culture medium of astrocytes treated with the PGE2
antiserum, but not exposed to TGF, indicating that the antiserum by
itself is unable to affect LHRH secretion.
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), PGE2-deficient T-CM
failed to induce LHRH release (Fig. 6). The addition of
PGE2, at a dose (2 ng/ml) that is ineffective when
administered in ADM, completely restored the response (Fig. 6),
indicating that T-CM contains a substance(s) able to facilitate the
stimulatory effect of the PG on LHRH release. In fact, this
substance(s) also appears to be present in CM (the culture medium of
control astrocytes not treated with TGF), because CM allowed this
normally ineffective dose of PGE2 to significantly enhance
LHRH release (Fig. 6).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In addition to this morphological substrate, it now appears clear that
hypothalamic astrocytes use trophic molecules of a peptidergic nature
to influence the development and secretory activity of LHRH neurons.
The glial growth factors shown to affect LHRH neuronal function to date
include TGF (5), bFGF (6, 11), TGFß1 (8), and, very recently (29),
neuregulins, members of the EGF family that initiate their actions by
interacting with EGFR-related receptors. Perhaps the most well
characterized of these polypeptides is TGF, which has been
demonstrated to be involved in the activation of LHRH release that
occurs during both normal puberty and sexual precocity induced by
hypothalamic lesions (10, 30). Rather surprisingly, LHRH neurons do not
contain measurable EGFR able to transduce the TGF signal (6, 13),
implying the participation of an intermediate cell type in the process
by which TGF stimulates LHRH release. As hypothalamic astrocytes
contain EGFR and respond to TGF with up-regulation of the TGF
gene (12), we postulated that astrocytes themselves are the cells that
mediate the effect of TGF on LHRH neurons (4, 5, 6, 12). The present
results support this concept, as they demonstrate the inability of
TGF (and EGF) to act directly on GT1-1 cells to elicit LHRH release
and the LHRH-releasing effectiveness of astrocyte culture medium
conditioned by exposure of the cells to either growth factor.
The lack of a direct TGF effect on LHRH release may not be
attributed to the short duration of the treatment (30 min), as a
similar cell line (GT1-7) does not respond to a much longer (4, 8, and
24 h) exposure to the growth factor (6). It is also unlikely that
higher doses of the growth factor would be effective, as a
1-µM concentration (6 µg/ml) of either TGF or EGF
failed to induce EGFR phosphorylation in GT1-7 cells, in contrast to
their effectiveness when administered to astrocyte cultures (6). We
cannot, however, rule out the possibility that LHRH neurons contain
functional EGFR at very specific developmental windows (for instance,
before or during migration) or that the receptors are present in a
(changing) subpopulation of mature LHRH neurons. The former possibility
is suggested by a recent report showing the presence of bioactive EGFR
in a LHRH neuronal cell line different from GT1 cells (31).
The results also demonstrate that one of the glial intermediates used
by TGF to elicit the release of LHRH is PGE2, and that
the effect of TGF on glial PGE2 synthesis requires the
intermediacy of EGFR. That products of the cyclooxygenase-dependent
metabolism of arachidonic acid are involved in mediating the effect of
TGF was demonstrated by the ability of indomethacin to prevent the
stimulatory effect of the astrocyte-conditioned medium on LHRH release.
The suppressive effect of specific immunoneutralization of
PGE2 in the conditioned medium and the ability of exogenous
PGE2 to restore the response identifies this PG as the
major cyclooxygenase product mediating the TGF effect on LHRH
release. The relevance of these findings to the normal hypothalamus is
indicated by the fact that median eminence fragments in
vitro also respond to TGF with PGE2 release and to
indomethacin with suppression of the TGF effect (5).
It does not appear that lipooxygenase products of glial arachidonic
acid metabolism are involved in the glia to neuron signaling mechanism
by which TGF promotes LHRH secretion. No changes in
LTC4, the major product of the lipooxygenase-mediated
pathway (23), were detected in astrocyte-conditioned medium 16 h
after the addition of TGF compared to that in untreated cultures.
NDGA, an inhibitor of lipooxygenase activity, did not affect these
basal levels of LTC4 and prevented the effect of the
TGF-conditioned medium on LHRH release only at doses that also
suppressed PGE2 levels. Ligand-dependent activation of EGFR
in other cell systems does result in the rapid synthesis of both
cyclooxygenase and lipooxygenase products (32, 33), suggesting that, if
astrocytes behave similarly, LTC4 levels may have already
returned to basal values after 16 h of exposure to TGF.
Whatever the case, the absence of elevated LTC4 levels in
the 16-h TGF-conditioned medium in the face of increased
PGE2 values strongly argues against a role for leukotrienes
in mediating the effect of TGF on LHRH release.
Although the present results provide clear evidence for an involvement
of astrocytic PGE2 in the glial-neuronal mechanism by which
TGF stimulates LHRH release, they also suggest the participation of
additional unidentified molecules in this process. PGE2 at
a concentration 3-fold higher than that detected in TGF-conditioned
medium failed to elicit LHRH release from GT1-1 cells, but it became
effective in the presence of control CM. Melcangi et al. (8)
showed that medium conditioned by immature astrocytes in culture
contains a thermostable factor able to release LHRH. The factor was
tentatively identified as TGFß. Although the ability of TGFß to
potentiate the effect of PGE2 on LHRH release remains
to be demonstrated, we noticed in preliminary experiments that a
general blocker of excitatory amino acid receptors eliminates the
potentiating ability of astrocyte-conditioned medium on
PGE2-induced LHRH release. Thus, it is possible that
excitatory amino acids released by astrocytes may be able to interact
with PGE2 in the control of LHRH secretion. Hypothalamic
astrocytes cultured in L-glutamine-containing ADM, do, in
fact, release the excitatory amino acids, aspartate and glutamate (Lee,
B. J., et al., unpublished data). Further experimentation is
required to identify the additional bioactive substance(s) released
from astrocytes that contributes to the TGF-mediated glial control
of LHRH release. It should also be mentioned that in the present
experiments, we did not observe a significant stimulatory effect of
control CM on LHRH release. As this effect has been detected after
exposing GT1 cells to CM for 1 h or longer (7, 8), our
results may be explained by the short exposure time (30 min) used.
At this point, it is important to recognize the emerging complexity of the glial-neuronal interactions that appear to control the secretory activity of LHRH neurons. Other growth factors acting via tyrosine kinase receptors, such as bFGF and neuregulins, have been recently shown to affect LHRH neuronal function (6, 11, 29). Although bFGF acts directly on LHRH neurons to facilitate neuronal differentiation, promote survival, and stimulate processing of the LHRH prohormone (6, 11), neuregulins stimulate LHRH release by inducing PGE2 formation in glial cells (29). Still other growth factors, such as TGFß, and insulin-like growth factors I and II have been shown to stimulate LHRH secretion (8, 34, 35). Although TGFß1 (8) and insulin-like growth factor II (35) appear to act directly on LHRH neurons, the stimulatory effect of IGF-I shown using median eminence fragments (34) may be indirect, as the peptide is unable to stimulate LHRH release from GT1 cells (35). In addition to this growth factor-mediated regulation, LHRH neurons themselves appear to regulate glial proliferation via releasable factors (7), suggesting the existence of an intricate bidirectional communication between LHRH neurons and glial cells, mediated by a variety of intercellular signaling molecules. Although the results of the above-described in vitro experiments need to be interpreted with caution, they do suggest that such an intercellular signaling process may also function in vivo. It is likely that the biochemical communication between glial cells and LHRH neurons is intimately associated with the well known changes in cell to cell contacts that occur between the two cell types during reproductive life (24, 27, 28).
The biological actions of PGE2 are initiated by binding of the PG to several membrane-anchored receptors (36). In recent experiments we demonstrated the presence of at least four types of PGE2 receptors in GT1-1 cells (37, 38). Among them, one subtype linked to calcium mobilization (EP1) has been identified by in situ hybridization techniques in LHRH neurons of immature animals (Rage, F., et al., unpublished data). Thus, it appears that LHRH neurons are endowed with the necessary recognition molecules to effectively transduce PGE2 signals derived from anatomically and functionally associated glial and neuronal networks.
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Acknowledgments |
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Footnotes |
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2 Postdoctoral Research Fellow supported by INSERM, France, and Grant
HD-25123. Present address: Lab Neurobiologie, Endocrinologique URA,
1197 CNRS Montpellier II, place Eugene Bataillon, 34090 Montpellier,
France.
Received July 15, 1996.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in the release of luteinizing-hormone releasing hormone from the
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) with prostaglandin E2 (PGE2) release.
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 B. Li, Z. Yang, J. Hou, A. McCracken, M. A. Jennings, and M. Y. J. Ma Compromised Reproductive Function in Adult Female Mice Selectively Expressing Mutant ErbB-1 Tyrosine Kinase Receptors in Astroglia Mol. Endocrinol., November 1, 2003; 17(11): 2365 - 2376. [Abstract] [Full Text] [PDF]
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 K. M. Dhandapani, V. B. Mahesh, and D. W. Brann Astrocytes and Brain Function: Implications for Reproduction Experimental Biology and Medicine, March 1, 2003; 228(3): 253 - 260. [Abstract] [Full Text] [PDF]
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B. Dziedzic, V. Prevot, A. Lomniczi, H. Jung, A. Cornea, and S. R. Ojeda Neuron-to-Glia Signaling Mediated by Excitatory Amino Acid Receptors Regulates ErbB Receptor Function in Astroglial Cells of the Neuroendocrine Brain J. Neurosci., February 1, 2003; 23(3): 915 - 926. [Abstract] [Full Text] [PDF]
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V. Prevot, C. Rio, G. J. Cho, A. Lomniczi, S. Heger, C. M. Neville, N. A. Rosenthal, S. R. Ojeda, and G. Corfas Normal Female Sexual Development Requires Neuregulin-erbB Receptor Signaling in Hypothalamic Astrocytes J. Neurosci., January 1, 2003; 23(1): 230 - 239. [Abstract] [Full Text] [PDF]
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S. K. Amateau and M. M. McCarthy A Novel Mechanism of Dendritic Spine Plasticity Involving Estradiol Induction of Prostaglandin-E2 J. Neurosci., October 1, 2002; 22(19): 8586 - 8596. [Abstract] [Full Text] [PDF]
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 S. R. Chiocchio, M. G.P. Gallardo, P. Louzan, V. Gutnisky, and J. H. Tramezzani Melanin-Concentrating Hormone Stimulates the Release of Luteinizing Hormone-Releasing Hormone and Gonadotropins in the Female Rat Acting at Both Median Eminence and Pituitary Levels Biol Reprod, May 1, 2001; 64(5): 1466 - 1472. [Abstract] [Full Text]
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 E. Terasawa and D. L. Fernandez Neurobiological Mechanisms of the Onset of Puberty in Primates Endocr. Rev., February 1, 2001; 22(1): 111 - 151. [Abstract] [Full Text]
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C. D. Buchanan, V. B. Mahesh, and D. W. Brann Estrogen-Astrocyte-Luteinizing Hormone-Releasing Hormone Signaling: A Rolefor Transforming Growth Factor-{beta}1 Biol Reprod, June 1, 2000; 62(6): 1710 - 1721. [Abstract] [Full Text]
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T. G. Harris, D. F. Battaglia, M. E. Brown, M. B. Brown, N. E. Carlson, C. Viguie, C. Y. Williams, and F. J. Karsch Prostaglandins Mediate the Endotoxin-Induced Suppression of Pulsatile Gonadotropin-Releasing Hormone and Luteinizing Hormone Secretion in the Ewe Endocrinology, March 1, 2000; 141(3): 1050 - 1058. [Abstract] [Full Text] [PDF]
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 K. J. Suter, C. R. Pohl, and M. E. Wilson Circulating Concentrations of Nocturnal Leptin, Growth Hormone, and Insulin-Like Growth Factor-I Increase before the Onset of Puberty in Agonadal Male Monkeys: Potential Signals for the Initiation of Puberty J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 808 - 814. [Abstract] [Full Text]
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Some Hypothalamic Hamartomas Contain Transforming Growth Factor {alpha}, a Puberty-Inducing Growth Factor, But Not Luteinizing Hormone-Releasing Hormone Neurons J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4695 - 4701. [Abstract] [Full Text]
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