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Department of Cell Biology, Neurobiology, and Anatomy, University of Cincinnati School of Medicine, Cincinnati, Ohio 45267-0521
Address all correspondence and requests for reprints to: Dr. Nira Ben-Jonathan, Department of Cell Biology, University of Cincinnati School of Medicine, 231 Bethesda Avenue, Cincinnati, Ohio 45267-0521.
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Abstract |
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Ovariectomized F344 rats were injected with 1 µg estradiol and killed at different times thereafter. Pituitaries were subjected to in situ hybridization for c-fos and immunostaining for selected pituitary cells. Estradiol stimulated c-fos expression in lactotrophs and folliculo-stellate cells within the anterior lobe without affecting either the intermediate or neural lobes. In a second experiment, c-fos messenger RNA levels were measured by solution hybridization in anterior pituitaries and uteri from estradiol-treated rats. Trunk blood was analyzed for PRL by RIA. The estrogen-induced c-fos rise in the uterus was rapid, robust, and transient, whereas that in the anterior pituitary was delayed, lower, and sustained. The profile of serum PRL levels resembles that of c-fos induction in the anterior pituitary.
We conclude that: 1) both lactotrophs and folliculo-stellate cells increase c-fos expression in response to estrogens; 2) induction of c-fos expression may mediate some estrogenic effects on PRL synthesis and release and lactotroph proliferation in F344 rats; and 3) the atypical dynamics of c-fos induction in the pituitary could be due to indirect effects of estrogens on PRL-regulating factors within the hypothalamo-pituitary complex as well as to pituitary-specific estrogen receptor isoforms, coactivators, or repressors.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The mechanism by which estrogens regulate such a variety of functions is poorly understood. In general, estrogens act by binding to intracellular receptors, causing them to undergo activation and dimerization. The estrogen-receptor complex binds to an estrogen response element (ERE) in target genes and modifies their transcription. An imperfect ERE sequence has been identified in the distal promoter region of the PRL gene (15), and substantial evidence indicates that estrogen directly stimulates PRL gene transcription (5, 16). However, PRL increases only 3- to 4-fold in response to estradiol in vitro (17, 18), whereas it often rises 10- to 20-fold after in vivo administration (19, 20). It is generally accepted that the direct action of estrogen on lactotrophs is augmented by altering hypothalamo-pituitary factors that affect the lactotrophs. These include hypothalamic dopamine (21, 22), PRL-regulating factor (PRF) from the intermediate lobe (23), and products of folliculo-stellate cells within the anterior lobe (24, 25).
The rat uterus has served as a model for studying the mechanism of action of estrogens. In this tissue, estrogens rapidly and transiently induce the expression of several immediate early genes, e.g. c-fos, c-myc, and c-jun, followed by activation of late genes associated with cell structure and metabolism (26). The product of c-fos is a nuclear protein that forms heterodimers with products of the jun gene family, generating the transcription factor, activating protein-1 (AP-1) (27). The induction of c-fos by estrogens is necessary, but insufficient, for mediating estrogen-induced cell proliferation in the uterus (28, 29). Further, although estrogen receptors are expressed in several uterine cell types, estrogens induce c-fos only in epithelia and glandular cells, but not in stroma or myometrium (28, 30).
Only limited information is available on the participation of c-fos as a mediator of lactotroph function. TRH (31, 32) and platelet-derived growth factor (31) induce c-fos gene expression in GH3 cells with a dynamics that parallels the rise in PRL messenger RNA (mRNA) levels. Prolonged treatment of male rats with estrogen increased the levels of PRL, c-myc, and c-fos mRNAs in the pituitary gland, an effect that was reversed by the dopaminergic agonist bromocriptine (33). Another group reported a rapid rise followed by a lower plateau in pituitary c-fos mRNA levels in response to estrogen treatment in vivo (34). Neither study identified which pituitary cells increase c-fos expression in response to estrogens.
The present experimental model was the estrogen-hypersensitive Fischer 344 (F344) female rat that develops hyperprolactinemia and prolactinomas in response to estrogen (19, 35). The objectives were to 1) determine whether lactotrophs, folliculo-stellate cells, and/or intermediate lobe cells increase c-fos gene expression in response to estrogen; 2) compare the dynamics of c-fos induction by estrogens in the pituitary and uterus; and 3) examine the temporal relationship between the induction of c-fos expression and the rise in PRL release.
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Materials and Methods |
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In situ hybridization for c-fos
In situ hybridization was performed as we previously
described (28). Briefly, frozen sections (10 µm) of pituitary glands
and uteri were mounted on slides, fixed in 4% paraformaldehyde,
dehydrated, and stored at -70 C. Before use, slides were treated with
proteinase K (20 µg/ml) for 3 min (uterus) or 10 min (pituitary) and
refixed. Slides were then treated with 0.25% acetic anhydride in 0.1
M triethanolamine for 10 min, washed, dehydrated, and
air-dried. The rat c-fos complementary DNA (a gift from Dr.
T. Curran, Roche Institute of Molecular Biology, Nutley, NJ) was cloned
into a pBluescript II SK+ (Stratagene, La Jolla, CA)
vector. Sense and antisense 35S-labeled riboprobes were
synthesized using the Promega riboprobe transcription kit (Promega,
Madison, WI). The riboprobes were treated with deoxyribonuclease for 15
min, alkaline hydrolyzed to 100- to 200-base fragments, purified on a
Sephadex G-50 column, ethanol precipitated, and resuspended in 0.2
M dithiothreitol (DTT).
The labeled probes (750,000 cpm) were heated in hybridization buffer [50% formamide, 0.3 M NaCl, 20 mM Tris (pH 8.0), 10 mM sodium phosphate (pH 8.0), 1 x Denhardt’s solution, 10% dextran sulfate, and 0.5 mg/ml yeast transfer RNA] and added to the tissue sections. Slides were coverslipped and incubated at 55 C for 13–18 h. Coverslips were removed, and the sections were washed in 50% formamide, 2 x SCC (standard saline citrate), and 10 mM DTT at 65 C for 30 min and washed three times with buffer A (0.5 M NaCl, 10 mM Tris, and 5 mM EDTA) for 10 min at 37 C. The slides were treated with 20 µg/ml ribonuclease A (RNase A) and 5–10 µg/ml RNase T1 for 30 min at 37 C and then washed with 1) buffer A for 15 min at 37 C; 2) 50% formamide, 2 x SCC, and 10 mM DTT at 65 C for 30 min; and 3) 2 x SCC, 1 mM DTT and 0.1 x SCC, 1 mM DTT. After dehydration and drying, slides were dipped in Kodak NTB2 emulsion (Eastman Kodak, Rochester, NY), stored at 4 C, and developed after 7–14 days.
Combined immunocytochemistry/in situ hybridization
Pituitary sections (10 µm) were mounted on slides and fixed in
4% paraformaldehyde as described above. All buffers and antibodies
were prepared in diethylpyrocarbonate-treated reagents. Sections were
rehydrated and rinsed in PBS containing 0.5% Triton-X-100. Slides were
treated with 0.5% hydrogen peroxide for 10 min to quench endogenous
peroxidase activity, and then incubated with 2% normal goat serum for
1 h. After removal of excess serum, slides were incubated with the
primary antibodies in a humid chamber at 4 C overnight. The rat PRL
antibody (NIH IC-5) was used at 1:15,000 dilution, and the S-100
antibody (Eastern Acres Biologicals, Southbridge, MA) was used at a
1:500 dilution. The latter served as a marker for folliculo-stellate
cells in the anterior lobe, marginal cells of the intermediate lobe,
and pituicytes of the neural lobe (36). After rinsing, slides were
incubated for 1 h with biotinylated secondary antibody and
avidin-biotin-peroxidase complex reagents according to instructions
using a peroxidase Vector kit (Vector Laboratories, Burlingame, CA).
Brown color was developed after the addition of diaminobenzidine for 5
min. After rinsing, slides were subjected to in situ
hybridization as described above. After develop-ment of the
photographic emulsion, slides were counterstained with hematoxylin.
Solution hybridization/RNase protection assay for c-fos
Total RNA was isolated from anterior pituitaries and uteri using
Tri-Reagent (MRC, Cincinnati, OH). The complementary RNA probes span
220 bp (nucleotides 68–287) for c-fos (37; gift from Dr. D.
Autelitano, Baker Medical Research Institute, Prahran, Australia) and
111 bp (nucleotides 36–146) for cyclophilin (gift from Dr. J. Roberts,
Mount Sinai School of Medicine, New York, NY). The RNA samples (5 µg)
were hybridized overnight at 45 C with the 32P-labeled
probes in hybridization buffer (80% formamide, 0.4 M NaCl,
40 mM PIPES, and 1 mM EDTA, pH 6.7). The
samples were then digested with RNase A (40 µg/ml) and RNase T1 (4100
U/ml) in digestion buffer (0.3 ml; 0.3 M NaCl and 10
mM Tris, pH 7.5). The hybrids were treated with proteinase
K (10 mg/ml) and 10% SDS for 15 min at 37 C, followed by
phenol/chloroform extraction and isopropanol precipitation. Hybrids
were resolved on nondenaturing 5% polyacrylamide gels.
Data analysis
Three separate pituitary sections from each time period (0 and
6 h) after estradiol injection immunostained for either PRL or
S-100 and hybridized for c-fos were used. In each section,
approximately 1000, 600, and 200 cells were counted within the
anterior, intermediate, and neural lobes, respectively. PRL- or
S-100-positive cells were enumerated, and the results were expressed as
the percentage of each cell type of the total number of cells counted.
A cell that contained seven or more silver grains was considered
positive for c-fos. The percentage of
c-fos-expressing lactotrophs was determined by dividing
cells positive for both PRL and c-fos by the total number of
lactotrophs. This was also performed for S-100-positive cells. In both
the intermediate and neural lobes, the percentage of
c-fos-positive, S-100-negative cells (designated "other"
cells) was also calculated. Results were expressed as the mean ±
SEM; differences between treatments were analyzed by
Student’s t test.
For the solution hybridization, radiolabeled bands were quantitated using a PhosphorImager and ImageQuant software (Molecular Dynamics, Sunnyvale, CA). The levels of c-fos mRNA were normalized to those of cyclophilin mRNA, and the results were expressed as fold stimulation over levels in control rats.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), c-fos expression in control (oil-treated)
rats was weak and diffuse in the anterior lobe, strong in the
intermediate lobe, and undetectable in the neural lobe. The expression
of c-fos in the anterior lobe increased within 2 h
after estrogen treatment, rose further by 6 h, and remained
elevated at 48 h. There was a tendency for a decrease in
c-fos mRNA in the intermediate lobe 6 h after estradiol
treatment, followed by a rebound. This pattern, however, was
inconsistent. Throughout this time period, there was no induction of
c-fos expression in the neural lobe. There was no specific
binding of the c-fos sense probe within the pituitary glands
of either control or estradiol-treated rats (Fig. 1).
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, c-fos expression was undetectable in the uteri of control
rats. Within 2 h after estradiol treatment, c-fos
expression increased markedly in the luminal and glandular epithelia,
returning to control levels after 24 h. No specific binding of the
c-fos sense probe was seen in uterine sections from either
control or estradiol-treated rats.
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, both
c-fos-positive (solid arrow) and negative
(open arrow) folliculo-stellate cells were apparent. Within
the intermediate lobe, S-100-positive cells (marginal cells) comprised
20% of the total cell number and were primarily localized in the
periphery of the lobules (Fig. 3B). Within the neural lobe,
S-100-positive cells (pituicytes) were diffusely distributed,
accounting for over 80% of the total cell number (Fig. 3C); only
occasional cells within the neural lobe were positive for
c-fos. As expected, lactotrophs were undetectable in either
the intermediate or neural lobes. Figure 3D demonstrates many clusters
of c-fos-positive (solid arrow) and some
c-fos-negative lactotrophs (open arrow) within
the anterior lobe.
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, left panel). Estradiol did not alter the
number of S-100-positive cells that also expressed c-fos in
the intermediate lobe (Fig. 4, middle panel). The number of
c-fos-positive cells in the intermediate lobe that were
negative for S-100 ("other" cells) showed a 50% decrease, but this
decline did not reach statistical significance. The number of
c-fos-expressing cells in the neural lobe (Fig. 4, right panel) was low (10–15% of total cells) and was not
altered by estradiol.
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and 6). In the anterior pituitary, the levels of
c-fos mRNA in control rats were low and did not change
within 1 h after estradiol treatment. This was followed by 3- and
5-fold rises at 2 and 24 h, respectively. Anterior pituitary
c-fos mRNA levels were still elevated 48 h after
estradiol treatment (Fig. 6, upper panel). The pattern of
c-fos induction by estradiol in the uterus was very
different. In control rats, uterine c-fos mRNA levels were
low, increased over 7-fold within 1 h after estradiol treatment
and were increased by over 20-fold at 2 h. The c-fos
expression decreased rapidly at 6 h, returning to control levels
by 24 h (Fig. 6, upper panel).
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(lower panel), serum
PRL levels increased 2-fold within 2 h of estradiol treatment,
rose 5-fold over control levels at 24 h, and remained elevated at
48 h. There was a marked similarity in the patterns of the
estradiol-induced rise in c-fos expression in the anterior
pituitary and serum PRL levels. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Many growth-promoting agents rapidly increase c-fos expression, with the Fos protein forming part of the AP-1 complex that functions as a transcription factor. The main effects of estrogens on the reproductive tract are stimulation of cellular growth, differentiation, and secretion. The uterus, where estrogen elicits a dramatic growth response, has been extensively used to document hormone- and cell-specific rises in c-fos expression (28, 30, 38). In contrast, mitogenic effects of estrogens in the neuroendocrine axis are significantly less profound, except for the marked pituitary enlargement due to lactotroph proliferation that is unique to the estrogen-hypersensitive F344 rat (19, 35). Using the OVEX F344 rat as the experimental model, the combined immunocytochemistry/in situ hybridization clearly showed a significant increase in the number of c-fos-expressing lactotrophs within 6 h of estrogen treatment. Moreover, the profile of plasma PRL levels during this period paralleled the rise in c-fos induction by estrogen. As the rat PRL gene contains consensus AP-1 binding sites in both proximal and distal promoter regions (39), it is reasonable to suggest that c-fos expression mediates some of the PRL rise in response to estrogen. To distinguish between an association of c-fos with PRL secretion and lactotroph proliferation, the estrogenic effects in F344 and other strains of rats with restricted proliferative response should be compared.
In addition to lactotrophs, several cell types within the pituitary gland are potential targets for estrogens. We focused on folliculo-stellate cells for several reasons. These cells, which are devoid of classical secretory granules, have long projections that form junctional complexes with endocrine cells, primarily lactotrophs (40). Folliculo-stellate cells have been reported to both stimulate (25, 41) and inhibit (42) the lactotrophs. They also exhibit dramatic structural changes in response to estrogen in F344, but not Sprague-Dawley, rats (24). The present data show that folliculo-stellate cells respond to estrogen by increased c-fos expression. Whether this rise is associated with vascular reorganization and angiogenesis, which precede estrogen-induced prolactinoma formation in F344 rats (24), or with regulation of the lactotrophs (25, 41, 42) remains to be determined. In agreement with a previous report (40), we found that folliculo-stellate cells comprise as much as a third of all anterior pituitary cells. Future studies should examine whether folliculo-stellate cells express estrogen receptors, and whether their effect on lactotrophs is augmented by treatment with estrogens.
As indicated previously, the S-100 protein also serves as a marker for marginal cells of the intermediate lobe (36). We reported that the intermediate lobe contains a subpopulation of cells that produce PRF (43) and mediates the acute estrogen-induced rise in PRL (20). This was supported by a recent study showing marked increases in PRF activity in neurointermediate lobe cells harvested from estrogen-treated F344, but not Sprague-Dawley, rats (44). In the present investigation we noted high expression of c-fos in the intermediate lobe of control rats. This could be due to constitutive expression of c-fos or its induction by the stress of handling and injection, as previously reported (45). Although there was a tendency for a decrease, followed by an increase, in c-fos expression after estrogen treatment, this pattern was not consistent. Because of the minute size of the neurointermediate lobe, we could not reliably quantitate these changes using the solution hybridization assay. This issue will be revisited in subsequent investigations.
In the uterus, the induction of c-fos by estrogen is rapid, robust, and transient. Such a profile is typical of the response induced by growth factors in other tissues (27). The rapid rise is probably due to a direct action of estrogen on uterine epithelial cells and binding of the activated estrogen receptor to an ERE sequence located in the 3'-flanking region of the murine c-fos gene (46). Mutations in this sequence that abolish binding of the estrogen receptor blocked estrogen activation of c-fos (47). The rapid decline has been attributed to Fos protein repressing its own gene, interference by Fos with further activation of the c-fos promoter by the estrogen receptor, as well as the very short half-life of the c-fos mRNA transcript (27, 48).
In contrast to the uterus, the induction of c-fos by estradiol in the anterior pituitary was delayed, lower, and sustained. A combination of factors may account for this atypical response. For instance, there might be tissue-specific differences in estrogen receptor isoforms, coactivators, or repressors. It has been reported that estrogen down-regulates its receptors in the uterus but up-regulates them in the pituitary gland (49). Two estrogen receptor isoforms, named TERP-1 and TERP-2, which lack the A/B, DNA-binding domain, hinge, and a small portion of the hormone-binding domain, have been identified in the rat pituitary and may mediate some estrogenic action in this tissue (50). To date, pituitary-specific estrogen receptor coactivators or repressors have not been identified.
The delayed activation of c-fos expression in the pituitary gland raises the possibility that some of the estrogenic effects are indirect, secondary to stimulation of hypothalamic or posterior pituitary factors that affect the c-fos gene by an ERE-independent mechanism. Using cultured primary anterior pituitary cells as well as GH3 cells, we were unable to demonstrate induction of c-fos by estradiol, although TRH and bromocriptine elicited transient increases and decreases, respectively, in c-fos mRNA levels (Allen, D. L. and N. Ben-Jonathan, unpublished observations). This supports the argument for an indirect effect of estradiol, although optimization of the culture conditions for the lactotrophs (51) may reveal some direct effects of estradiol.
The sustained elevation of c-fos mRNA in response to estrogen in the pituitary gland may result from sequential activation of autocrine/paracrine factors (e.g. galanin and vasoactive intestinal peptide) by estrogen, which could continue to induce the c-fos gene or stabilize its transcript. In addition to ERE, several cis elements, such as a cAMP response element and a serum response element, have been mapped to the c-fos gene (52). In summary, more information is needed on the cellular distribution, structure, and signalling pathways of estrogen receptors within the pituitary gland before a functional relationship among estrogen, c-fos expression, PRL synthesis, and lactotroph proliferation is established.
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Acknowledgments |
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Footnotes |
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2 Present address: Department of Physiology and Biophysics, Indiana
University School of Medicine, Myers Hall 152, Bloomington, Indiana
47405.
Received December 9, 1996.
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