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and ß in the Rat Pituitary Gland1
Department of Cell Biology, University of Cincinnati Medical School, Cincinnati, Ohio 45267
Address all correspondence and requests for reprints to: Dr. Nira Ben-Jonathan, Department of Cell Biology, University of Cincinnati Medical School, 231 Bethesda Avenue, Cincinnati, Ohio 45267-0521.
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Abstract |
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. However, a novel
receptor, ERß, and pituitary-specific truncated estrogen receptor
products (TERPs) were recently identified. The objectives of this study
were to examine the distribution of these receptors in the rat
pituitary and compare their regulation by estradiol in
Sprague-Dawley and the estrogen-sensitive Fischer 344
rats.
Pituitary cryosections were subjected to immunocytochemistry for
specific cell types, followed by in situ hybridization
for ER or ERß. ER was expressed by approximately 45% of the
lactotrophs and melanotrophs, 35% of the corticotrophs and
folliculo-stellate cells, and 25% of the gonadotrophs. The expression
of ERß showed a similar pattern but was generally lower than ER.
In two cell types, melanotrophs and gonadotrophs, ERß expression was
significantly lower than ER. In the second experiment, pituitary
sections were immunostained for ER, followed by in
situ hybridization for ERß. Only a minute population
(6–10%) of either anterior or intermediate lobe cells coexpressed
ER and ERß. In the next experiment, Fischer 344 and Sprague-Dawley
rats were injected with oil or estradiol for 24 h. Total RNA from
dissected anterior and posterior (neurointermediate) pituitaries was
subjected to RT-PCR for ER, ERß, or TERPs. Interestingly, ER
and ERß were unchanged by estradiol in either lobe of the pituitary.
In contrast, estradiol increased pituitary TERP messenger RNA levels 4-
to 7-fold. A 20-kDa TERP protein was detected by Western blots in the
pituitary but not the uterus. There were no differences in the
estradiol-induced expression of any of the receptors between the two
strains of rats.
We conclude that: 1) ERß is expressed in all anterior and
intermediate lobe cell types examined, albeit at a lower level than
ER; 2) no more than 10% of pituitary cells coexpress ER and
ERß; and 3) estradiol markedly increases TERP messenger RNA levels
but does not alter the expression of ER or ERß. We propose that
estrogen receptor heterogeneity contributes to the diversity of
pituitary cell responsiveness to estrogens.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), which has been localized to most
pituitary cells (8), is thought to mediate the direct effects of
estrogen in the pituitary.
As depicted in Fig. 1
, ER is comprised
of five functional domains: a DNA binding domain (DBD), a hinge region,
a hormone binding domain (HBD), and two transactivation domains (AF-1
and AF-2). Upon ligand activation, the receptor dimerizes, binds to a
consensus DNA sequence named the estrogen response element (ERE), and
alters gene transcription (reviewed in Refs. 9, 10). Several ER
isoforms have been identified, especially in cancer cells (11, 12), but
their function remains unclear. The rat pituitary expresses truncated
estrogen receptor products (TERPs) that have not been detected in other
tissues (13, 14, 15, 16). These receptors are truncated at exon 5 and have two
isoforms, TERP1 and TERP2. The more abundant TERP1 has a unique 31-bp
sequence, whereas TERP2 contains the same sequence as TERP1 with an
additional 66 bp (Fig. 1). Neither the specific pituitary cells
expressing TERP nor its function are known.
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, respectively (see Fig. 1
), exhibits high affinity for
estradiol and binds to the same ERE as ER (18, 19). The
dissimilarity in the two transactivation domains between ER and
ERß raises the possibility of a different pattern of gene activation
by the two receptors. Because ER and ERß can form heterodimers
in vitro (20), they may also act together to regulate gene
transcription. Since its discovery, ERß expression has been
demonstrated in a variety of tissues, including the pituitary gland
(18), but the exact cellular distribution of ERß within the pituitary
has not been reported. The pituitary of Fischer 344 (F344) rats is especially sensitive to exogenous estrogens. Prolonged exposure to estrogens results in hyperprolactinemia and formation of prolactinomas in F344, but not in other rat strains (6, 21, 22, 23). This estrogen sensitivity of F344 rats is pituitary-specific, because their uterus does not undergo unusual changes in response to estrogen. In spite of a significant interest in this rat strain as a model for prolactinoma formation, the mechanism underlying the heightened sensitivity to estrogens is unknown (21, 24).
The purpose of this work was to determine the cellular distribution of
estrogen receptors in the rat pituitary and examine their regulation by
estradiol. The objectives were to: 1) identify the specific pituitary
cells that express ER and ERß; 2) determine whether these
receptors are coexpressed in the same cell; and 3) compare estrogen
regulation of ER, ERß, and TERPs in the pituitaries of F344 and
Sprague-Dawley (SD) rats.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Combined immunocytochemistry/in situ hybridization
Dual immunocytochemistry/in situ hybridization was
performed as previously described (4). Briefly, frozen pituitary
sections (10 µm) from SD rats were mounted on slides and fixed with
4% paraformaldehyde. All solutions and antibodies were prepared with
diethylpyrocarbonate-treated reagents. Sources of the polyclonal
antibodies and their dilutions are as follows: PRL (NIH IC-5) at
1:15,000; S100 (a marker for folliculo-stellate cells; Eastern Acres
Biologicals, Southbridge, MA) at 1:500; POMC (a marker for both
melanotrophs and corticotrophs; gift from Dr. B. Eipper, John
Hopkins University, Baltimore, MD) at 1:1,000; LH no. 15 (gift
from Dr. G. Niswender, Colorado State University, Fort Collins, CO) at
1:25,000; and ER 21 (gift from Dr. G. Greene, University of Chicago,
Chicago, IL) at 0.5 µg/ml. Antibodies were incubated overnight at 4
C. Staining was obtained using biotinylated-secondary antibodies and
avidin-biotin-peroxidase complex (ABC kit, Vector Laboratories,
Burlingame, CA). Brown color was developed after adding
diaminobenzidine for 2 min.
The immunostained sections were subjected to in situ
hybridization. The slides were treated with proteinase K, refixed, and
incubated with acetic anhydride, as previously described (4). The ER
riboprobe was prepared from a 415-bp subclone (1–415 bp) of a rat
ER complementary DNA (gift of Dr. M. Shupnik, University of
Virginia, Charlottesville, VA). The ERß riboprobe was prepared by PCR
cloning of a 305-bp segment (941–1246 bp) from rat hypothalamus.
Sequencing was performed to confirm specificity. Sense and antisense
probes for the two receptors were labeled with 35S using a
Promega (Madison, WI) in vitro transcription kit and were
purified on a Sephadex G-50 column. Slides were hybridized at 55 C,
using 750,000 cpm of either probe per section, extensively washed and
dipped in Kodak NTB2 emulsion (Eastman Kodak, Rochester, NY).
After 5 days at 4 C, the photographic emulsion was developed, and the
slides were counterstained with hematoxylin.
RT-PCR
Total RNA was isolated from individual anterior or posterior
pituitaries using Tri-reagent (Molecular Research Center, Cincinnati,
OH), and 5 µg were reverse-transcribed using Superscript II reverse
transcriptase and random hexamers (Gibco, BRL, Gaithersburg, MD), as
previously described (25). Primer sequences and the expected product
sizes were as follows: 1) ER: sense primer
5'-GGTCCAATTCTGACAATCGAGC-3', antisense primer
5'-TTTCGTATCCCGCCTTTCA-TC-3' with an expected size of 304 bp; 2)
TERP: sense primer 5'- GCTTGTTGAACAGCGACCAG-3', antisense primer
5'-CTTGTCCAGGACTCGGTG-3' with expected sizes of 366 bp for TERP1 and
432 for TERP2; and 3) ERß: sense primer 5'-AACACTTGCGAAGTCGGCAG-3',
antisense primer 5'-AACCTCAAAAGAGTCCTTGGTGTG-3' with an expected size
of 327 bp. Location of primers for the different estrogen receptors is
shown in Fig. 1. All reactions also contained primers for ribosomal
protein L19 (RPL19) as an internal control; sense primer
5'-AGTAGTCTTAGGCTACAGAAG-3', antisense primer
5'-TTCCTTGGTCTTAGACCTGCG-3' with an expected size of 500 bp.
Optimal conditions for PCR were established after varying the RNA
concentration, annealing temperature, and cycle number for each set of
primers. For ER, 300 ng RNA were amplified at 58 C for 28 cycles.
For TERPs, 500 ng RNA were amplified at 55 C for 28 cycles. For ERß,
500 ng RNA were amplified at 62 C for 30 cycles. PCR products were
separated on a 1% agarose gel stained with ethidium bromide,
photographed, and analyzed by scanning densitometry (Scion Image
Software, Frederick, MD).
Western blotting
Pituitary and uterine tissues were removed from control and
estradiol-treated rats and immediately frozen. Tissues were homogenized
in a buffer (50 mM Tris-HCl (pH 7.5), 150 mM
NaCl, 5 mM EDTA) containing protease inhibitors [0.1
mM phenylmethlysulfonylflouride (Sigma, St Louis, MO), 20
mM sodium molybdate (Sigma), and 50 µg/ml lima bean
trypsin inhibitor (Worthington Biochemical, Freehold, NJ)] and
centrifuged at 13,000 x g for 10 min. After protein
determination, using a Pierce (Rockford, IL) BCA protein assay, 30 µg
of proteins were separated by SDS-PAGE (12% separating gel).
Recombinant human ER (hER) (50 ng), purchased from PanVera
(Madison, WI), was used as a positive control. Proteins were
transferred to nitrocellulose membranes (Schleicher and Schuell, Keene,
NH), followed by Ponceau S staining to verify transfer. After blocking
in 2% nonfat milk for 2 h, blots were incubated overnight at 4 C
with polyclonal antibody against ER (C1355; gift from Dr. M.
Shupnik) at 1:7,500. This antibody was raised against the extreme
C-terminus of the receptor protein (16) (see also Fig. 1). An ECL kit
(Amersham, Arlington Heights, IL) was used to visualize the
products.
Data analysis
Four separate sections from 3–4 rats, each immunostained for a
pituitary cell type, were used for the determination of ER and ERß
gene expression, by in situ hybridization. A cell was
considered receptor-positive if 5 or more grains were located within
the cell perimeter; background levels with the sense probe were 2–3
grains/cell. Approximately 1000 and 600 immunopositive cells (brown
staining within the cytoplasm) in the anterior and intermediate lobes,
respectively, were counted for each receptor. The percentage of
receptor-expressing cells was determined by dividing the number of
cells positive for both the receptor and the immunogen by the total
number of immunopositive cells. For determination of anterior or
intermediate lobe cells that express ER and/or ERß, 4 separate
sections from 3 rats were first immunostained for ER and then
subjected to in situ hybridization for ERß. Determination
of receptor expression was done as described above, except that
ER-expressing cells were identified by brown nuclear staining. In
all cases, cell counting was performed by 2–3 investigators, and the
values were averaged.
For RT-PCR determination, the density ratio of receptor/RPL19 bands was analyzed for each reaction product, and the results were expressed as percent of control values.
All results are expressed as the mean ± SEM. Statistical differences were determined using ANOVA (Sigma Stat 4.0), followed by either Duncan’s or Student-Newman-Keuls post hoc tests.
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Results |
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and ERß in the uterus and ovary shows representative
dark-field photomicrographs of rat uterus and ovary subjected to
in situ hybridization for ER and ERß, respectively. As
expected, ER-expressing cells are abundant in the luminal and
glandular epithelia, as well as in the myometrium of the uterus
(left panel), whereas ERß-expressing granulosa cells are
apparent within ovarian follicles (right panel). This
pattern conforms with published results (17, 26) on the differential
expression of the two receptors in these tissues. Sense probes showed
no detectable labeling above background (not shown).
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and ERß in different pituitary cell types and ERß by specific pituitary
cells, we used a combined immunocytochemistry/in situ
hybridization method. Fig. 3 shows
cellular details of lactotrophs within the anterior pituitary
(left panel) and melanotrophs within the intermediate lobe
(right panel) that express each of the receptors; similar
data (not shown) were obtained for gonadotrophs, corticotrophs, and
folliculo-stellate cells. The percentage of each cell type that
expresses either ER or ERß is summarized in Fig. 4. Approximately 47% and 27% of the
lactotrophs express ER and ERß, respectively, whereas 35% of the
corticotrophs express ER, and 25% express ERß. A similar number
of folliculo-stellate cells (30–35%) express either receptor, whereas
gonadotrophs had a significantly (P < 0.05) higher
expression of ER (26%) than ERß (17%). Within the intermediate
lobe, a significantly (P < 0.05) higher number of
melanotrophs express ER (43%) than ERß (23%).
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and ERß in pituitary cells
shows photomicrographs of anterior (left panel) and
intermediate (right panel) lobes depicting cells that
express ER, ERß, or both. As summarized in Fig. 6, 38% of anterior pituitary cells are
positive for the ER protein, whereas 20% express ERß messenger
RNA (mRNA). Notably, only 8–10% of anterior pituitary cells coexpress
both ER and ERß. Similarly, 37% of the intermediate lobe cells
are positive for the ER protein, 14% are positive for ERß mRNA,
and only 6% of the cells are positive for both receptors.
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. Because optical densities for both
RPL19 and TERP1 increased in a linear fashion between 25–30 cycles
(Fig. 7, left panel), 28 cycles were selected for further
experiments. The right panel shows that the optical density
for both genes was linear up to 500 ng of RNA. Because these results
were obtained from a maximally-stimulated pituitary, 500 ng RNA were
used in subsequent experiments. Fig. 7 (lower panel) also
shows a photograph of PCR products for TERPs in the anterior pituitary,
demonstrating a substantial increase in the expression of the two
truncated receptors, in response to estradiol.
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summarizes receptor regulation
by estradiol in the anterior and posterior pituitaries from F344 and SD
rats. Within 24 h of estradiol treatment, TERP1 mRNA levels rose
5- to 7-fold above controls (P < 0.05) in either the
anterior or posterior pituitaries. The less abundant TERP2 increased 3-
to 5-fold above control (P < 0.05), in response to
estradiol in the anterior pituitary, but was not significantly higher
than control in the posterior pituitary. Unexpectedly, the expression
of ER or ERß was not altered by estradiol in either lobe of the
pituitary. Although estradiol treatment decreased ERß levels in the
anterior pituitary of F344 rats to 50% of controls, this change did
not reach statistical significance. There were no significant
differences between the two strains of rats in the ability of estradiol
to induce any of the receptors.
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(see Fig. 1) was used for Western blots of pituitary and uterine
proteins. Figure 9 shows the detection of
a full-length ER (66 kDa) in the pituitary, uterus, and recombinant
hER. The TERP protein (20 kDa) was detected in the pituitary, but
not uterus, confirming a previous report by Friend et al.
(16). Interestingly, TERP was also detected in a control pituitary,
without an apparent increase after estradiol treatment. Another
immunoreactive product (approximately 50 kDa) was seen in the
estradiol-treated, but not control, uterus.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and ERß in identified pituitary cells and to determine whether
any cells coexpress the two receptors. In addition, we investigated
whether these receptors are regulated by estradiol.
The lactotrophs, which constitute 25–40% of total anterior pituitary
cells (29), are well recognized as a major target for estrogens.
Several lines of evidence established that estrogens increase PRL gene
expression, synthesis, storage, and release, as well as lactotroph
proliferation (30). Our data demonstrate that approximately 50% of the
lactotrophs express ER whereas less than 30% express ERß. Given
the marked heterogeneity of the lactotrophs, in terms of electrical
activity, hormone storage, responsiveness to secretagogues, and
morphology (reviewed in Refs. 31, 32), it is conceivable that
certain subpopulations of lactotrophs express little or no estrogen
receptors.
Folliculo-stellate cells constitute 25–30% of anterior pituitary
cells (4). These cells, which are devoid of classical hormones, form
junctional complexes with hormone-secreting cells (33) and may affect
their function via paracrine or juxtacrine interactions (34).
Folliculo-stellate cells are likely targeted by estrogen, as
exemplified by a rapid increase in c-fos expression (4) and
marked structural changes in these cells (5) in response to estrogen.
Our results demonstrate, for the first time, that at least one third of
the folliculo-stellate cells express ER or ERß, suggesting a
direct action of estradiol on these cells.
The reproductive hormones LH and FSH are under positive and negative regulation by estrogens. Although the major consensus is that estrogen primarily alters the release of GnRH, estrogen also induces GnRH receptor gene expression in the gonadotrophs (35) and alters their responsiveness to GnRH (3). Interestingly, the majority of gonadotrophs, which constitute 5–10% of the total anterior pituitary cells (36), do not express estrogen receptors. The paucity of estrogen receptors in the gonadotrophs supports the notion that the main action of estrogen affecting the gonadotrophs is via the hypothalamus.
We and others (7, 37, 38, 39) previously reported that the intermediate
lobe mediates estrogen-induced PRL surges and that estrogen treatment
in vivo increases PRL regulating factor activity in cultured
posterior pituitary cells (6). Using an oligonucleotide probe against
ER, Pelletier et al. (28) detected estrogen
receptor-expressing cells within both the anterior and intermediate
lobes but not the neural lobe. We found that more than 40% of the
melanotrophs express ER, whereas only 20% express ERß. It remains
to be determined whether the estradiol-induced increase in
PRL-regulating factor activity in the intermediate lobe is mediated by
either of these receptors. Because the POMC antibody also immunostained
the corticotrophs, we examined receptor expression by these cells and
found that 20–30% of the corticotrophs expressed either of the
estrogen receptors. However, there is little, if any, evidence for a
direct action of estrogen on the function of the corticotrophs.
Our data on the distribution of ER-expressing cells agree with
previous reports that most pituitary cells express ER (8, 27). The
combined immunocytochemistry/in situ hybridization approach
provides high resolution, is well-suited for identifying and
enumerating specific cells within an intact pituitary gland, but has
some unavoidable limitations in terms of quantitation.
The novel aspect of this investigation is the detection of ERß expression in all pituitary cell types examined. It is of interest that Kuiper et al. (18) reported expression of ERß in the rat pituitary, as determined by RT-PCR, whereas Couse et al. (40) did not detect its expression in the mouse pituitary using ribonuclease protection assay. The disagreement between these findings could be caused by species variation, because we were unable to detect ERß in a mouse pituitary using RT-PCR (Mitchner et al., unpublished observations).
ERß is predominantly expressed in tissues such as the ovary (41),
prostate (17), bone (42), and brain (43, 44). Although the activated
ER and ERß seem to bind to the same ERE (18), it is unclear
whether they exhibit distinct, overlapping, synergistic, or
antagonistic actions. As determined by a mammalian two hybrid system,
ER and ERß can form heterodimers (20), suggesting an alternate
signaling pathway by which the two receptors may act. However, such a
mechanism requires that the two receptors are coexpressed by the same
cell. Using immunocytochemistry for ER and in situ
hybridization for ERß, we found coexpression in a minority (8–10%)
of either anterior or intermediate lobe cells. It is possible that such
coexpressors represent only one cell type, i.e. lactotrophs
or gonadotrophs. To resolve this issue, a challenging triple-labeling
technique, which is presently under development, must be employed.
A ligand may up- or down-regulate its receptors, depending on the
tissue and physiological conditions. Shupnik et al. (14)
reported that ER mRNA levels increased in the uterus, but decreased
in the pituitary, following ovariectomy, whereas estrogen replacement
reversed the effect of ovariectomy in both tissues. The same group also
discovered the existence of a pituitary-specific truncated ER,
termed TERP, at both the mRNA (15) and protein (16) levels. The latter
finding is of significance because many splice variants of the estrogen
receptor, detected primarily in tumors, have not been confirmed at the
level of the receptor protein.
The minute size of the rat pituitary, especially the posterior
pituitary, necessitates a very sensitive detection method. To this end,
we optimized an RT-PCR method for quantifying alterations in receptor
expression. We found that TERP expression was significantly increased
in response to estradiol, whereas ER was unaltered. Shupnik et
al. (14) initially reported an estrogen-induced rise in total
pituitary ER mRNA levels that included both the wild-type and TERP. In
a subsequent study, the same investigators (16) observed a dramatic
increase in TERP mRNA levels in the afternoon of proestrus, presumably
caused by the rising estradiol levels. Collectively, these results
suggest that the overall increase in ER expression, in response to
estradiol, can be attributed to TERP. A lack of effect of estradiol on
the levels of immunoreactive ER in the monkey pituitary was also
reported (45). Interestingly, the present study also shows that
estradiol did not alter the expression of ERß in either the anterior
or posterior pituitaries.
The up-regulation of pituitary TERP expression by estradiol raises several issues. The first concerns the identity of cells in which TERP mRNA is induced. This is presently difficult to resolve because of the absence of selective tools, e.g., antibodies or probes, for TERP identification. The second concerns the function(s) subserved by this receptor, which lacks the DBD but may still bind estrogen and form heterodimers with the wild-type receptor. We speculate that TERP acts either as a sink for estrogen or as a dominant-negative regulator of the wild-type receptor. Our preliminary results (Mitchner et al., unpublished observations) indicate that TERP mRNA levels increase in response to estradiol in GH3 cells, a somatomammotroph cell line. This observation suggests that TERPs are expressed in the lactotroph and provides an excellent cellular model for examining their function(s).
We found no significant differences in receptor regulation by estradiol between the two strains of rats. Thus, the enhanced sensitivity of the F344 pituitary to exogenous estrogens may not be attributed to differences in the level of expression of the estrogen receptor. Instead, it could be caused by differences in receptor signaling involving coactivators or suppressors.
In conclusion, we have shown that ER and ERß are expressed, in
varying proportions, in all anterior and intermediate lobe cells
examined. In general, the expression of ERß was lower than ER.
Only a minor population of cells coexpresses the two receptors. Whereas
estradiol did not alter the expression of ER or ERß, TERP was
increased 5- to 8-fold. These results suggest that estrogen receptor
heterogeneity contributes to the diversity of pituitary cell
responsiveness to estrogen. Further investigations should delineate the
exact roles of each of these receptors in activating target genes in
specific pituitary cell types.
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Acknowledgments |
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Footnotes |
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Received March 6, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and ß. Endocrinology 138:863–870 and ERß at AP1 sites. Science 277:1508–1510. Mol Endocrinol 11:1486–1496 (ER) and estrogen receptor-ß (ERß) messenger
ribonucleic acid in the wild-type and ER-knockout mouse.
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