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in the Anterior Pituitary Gland
Howard Hughes Medical Institute (K.M.S., A.S.G., M.G.R.),
Department and School of Medicine, University of California, San
Diego, La Jolla, California 92093-0648,
Receptor Biology
Section (J.L., K.S.K.), Laboratory of Reproductive and Developmental
Toxicology, National Institute of Environmental Health Sciences,
Research Triangle Park, North Carolina 27709,
Departments of
Biochemistry and Child Health (D.B.L.), University of Missouri,
Columbia, Missouri 65211
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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(ER) gene has provided a genetic model in
which to test hypotheses that estrogens exert important effects in
development and homeostatic functions of the anterior pituitary gland,
particularly in the lactotroph and gonadotroph cell types. Analysis of
ER gene-disrupted mice reveals a marked reduction in PRL mRNA and a
decrease in lactotroph cell number, but normal specification of
lactotroph cell phenotype. Gonadotropin mRNA levels in ER
gene-disrupted female mice are elevated, consistent with previously
described transcriptional suppression of gonadotropin subunit gene
expression in response to sustained administration of estrogen in wild
type mice. These results provide genetic evidence that ER plays a
critical role in PRL and gonadotropin gene transcription and is
involved in lactotroph cell growth, but is not required for
specification of lactotroph cell phenotype. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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In lactotroph cells, estrogens have been proposed to be involved in specification of cell phenotype, growth, and synthesis and secretion of PRL. Ontogenic analyses have correlated ER expression with the onset of PRL gene expression in the embryo and with a postnatal increase in lactotroph cell number (2, 6, 7, 8). Estrogens have been shown to stimulate lactotroph cell growth (9, 10) and PRL secretion (11, 12), as well as having been linked to the development of PRL-secreting pituitary tumors (13). A number of molecules have been hypothesized to mediate these effects: vasoactive intestinal peptide (14), galanin (15), and transforming growth factor-ß3 (16). Additionally, numerous lines of independent evidence indicate that mature lactotroph cells are derived from somatotroph cells, possibly through an intermediate cell type that coexpresses both GH and PRL (17, 18, 19, 20, 21, 22, 23, 24).
Ligand-bound ER has been demonstrated to activate PRL transcription via direct interaction with the PRL gene distal enhancer (25, 26, 27). Treatment with estrogen results in increased nuclease hypersensitivity of the PRL promoter and increased interaction of the promoter with the PRL distal enhancer (28, 29, 30). Transcriptional activation of PRL gene expression by ER involves synergism with the pituitary-specific POU domain factor, Pit-1, bound to a monomer DNA recognition site that dictates use of a tyrosine-dependent synergy domain in Pit-1 (2, 31, 32, 33).
Regulation of gonadotropin synthesis and secretion is mediated by
GnRH from the hypothalamus, gonadal peptides, and classical feedback
effects by gonadal steroids (34). Although an estrogen surge during
proestrus can directly induce transcription of LHß mRNA (35), chronic
treatment of animals with estrogens results in suppression of
expression of all three gonadotropin subunit genes — LHß, FSHß,
and -glycoprotein subunit (GSU) (36). The majority of evidence
suggests that suppression of gonadotropin synthesis by chronic estrogen
treatment is mediated indirectly via decreased hypothalamic GnRH
secretion or altered pituitary responsiveness to GnRH (37, 38, 39, 40, 41, 42, 43, 44).
However, the level at which estrogens regulate gonadotropin synthesis
is species-dependent. In the rat, gonadotropin synthesis in isolated
pituitaries in culture shows no response to estrogen while GnRH mRNA
levels in cultured hypothalamic explants decrease in response to
estrogen (34). In sheep, in contrast, estrogen has been shown to
suppress FSHß subunit transcription in isolated pituitary cell
cultures (45).
The ER gene-disrupted mouse has provided a genetic model in
which to test hypotheses regarding the role of estrogens in the
development and function of the anterior pituitary (46). The ER
gene-disrupted mice undergo normal prenatal sexual development and
survive to adulthood, but both genders are completely infertile. Mutant
females possess hypoplastic uteri and hyperemic ovaries with no
detectable corpora lutea (46), have circulating estradiol levels that
are 10-fold higher than wild type females (47), and exhibit alteration
of gender-specific behaviors (48). Mutant males possess small testis,
dysmorphogenic seminiferous tubules, and low sperm count (49). In this
report, we examine the effect of a targeted insertional disruption of
the mouse ER gene on differentiation of endocrine cell types and
trophic hormone gene expression in the anterior pituitary gland.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Gene-Disrupted and Wild Type
Female Mice gene disruption on the
expression of genes encoding markers of terminal differentiation,
Northern analysis was used to compare steady state levels of mRNAs
encoding all of the anterior pituitary trophic hormones in wild type
and ER gene-disrupted mice (Fig. 1
). Total RNA was
isolated from pooled pituitaries of wild type and ER gene-disrupted
4-month-old non-parous female mice.
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gene-disrupted mice
relative to wild type controls, providing genetic evidence in support
of a positive role for ER in activation of PRL gene expression
(25, 26, 27, 28, 29, 30, 31, 32, 33). Transcripts encoding all of the gonadotropin subunits were
increased in the ER gene-disrupted mice relative to wild type
controls. Messenger RNA levels of the common GSU subunit increased
4-fold in the ER gene-disrupted mice, while transcripts encoding the
unique subunits of the gonadotropins, LHß and FSHß, both increased
almost 7-fold. This outcome is in agreement with data obtained in
numerous studies using gonadectomy and estrogen replacement in which
removal of the ovaries resulted in increased expression of all three
gonadotropin subunit mRNAs, and subsequent administration of estrogen
coordinately suppressed gonadotropin mRNA levels (50). Levels of POMC,
TSHß, and GH mRNAs all increased to a small degree in the ER
gene-disrupted mice relative to wild type mice, although it is
difficult to ascribe biological significance to these results.
Comparison of Gonadotropin and PRL mRNA Levels in ER
Gene-Disrupted and Ovariectomized Wild Type Mice to Intact Wild Type
Mice
To evaluate the difference in the effect on anterior pituitary
trophic hormone gene expression that resulted from hereditary ER
gene disruption vs. acute loss of estrogenic ligands,
changes in steady state levels of mRNAs encoding the trophic hormones
LHß, FSHß, and PRL from ER gene-disrupted mice were compared by
Northern analysis to the changes in mRNA levels that occurred in wild
type mice of the same age and gender that had been ovariectomized 10 to
14 days before death (Fig. 2). In both
the ER gene-disrupted and the ovariectomized wild type mice, LHß
and FSHß mRNAs increased to approximately equivalent levels compared
to intact wild type mice. These data indicated that a transient
decrease in estrogen produced by removal of the main site of estrogen
synthesis, the ovaries, had essentially the same effect on the levels
of LHß and FSHß mRNAs as hereditary ER gene disruption. In the
case of PRL transcripts, however, the decrease in steady state
transcript level in the ovariectomized mice, approximately 2-fold, was
not as large as the decrease seen in the ER gene-disrupted mice,
which was more than 10-fold. This result suggested that for PRL gene
expression, the effect of hereditary ER gene disruption was more
profound than acute loss of estrogenic ligands.
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Gene-Disrupted and Wild Type Male Mice gene-disrupted
mice to identify a possible gender difference in the requirement for
ER in generation of normal PRL mRNA levels. Northern analysis was
used to compare the steady state level of PRL mRNA in ER
gene-disrupted mice and wild type control mice (Fig. 3). As in the case
of the female ER gene-disrupted mice, however, there was a large
decrease of approximately 10-fold in the PRL mRNA levels of male ER
gene-disrupted mice.
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Gene-Disrupted Mice gene disruption on growth of
specific cell types and secretion of trophic hormones, pituitary glands
of wild type and ER gene-disrupted adult female mice were sectioned
and immunostained with antisera directed against the trophic hormones
elaborated by each of the five endocrine cell types. The patterns of
immunostaining of all three gonadotropin subunit proteins (GSU,
LHß, and FSHß) were altered in the ER gene-disrupted mice
relative to wild type controls (Fig. 4A). Immunostaining of GSU, the
common subunit of LH, FSH, and TSH, revealed a moderate increase in
cell density in the ER gene-disrupted mice relative to wild type
control mice. An increase in cell density was also noted in the ER
gene-disrupted mice with TSHß immunostaining, but no change was
observed with LHß or FSHß immunostaining. In the case of LHß, the
intensity of cytoplasmic staining in the ER gene-disrupted mice was
significantly decreased relative to wild type mice, suggesting that
ER may normally exert a suppressive effect on LH secretion. FSHß
immunostaining in the ER gene-disrupted mice was similar to the wild
type mice with the exception of a small number of cells in the ER
gene-disrupted mice that displayed increased intensity of cytoplasmic
staining.
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normally exerts a positive effect on lactotroph cell growth (Fig. 4B
).
Among immunoreactive PRL cells, however, no difference in intensity of
cytoplasmic staining was observed between ER gene-disrupted and wild
type mice. Immunostaining with antisera directed against ACTH revealed
a moderate increase in cell density in ER gene-disrupted mice
relative to wild type controls, but no change was detected with GH
antisera.
Lactotroph Cell Phenotype Specification in ER Gene-Disrupted
Mice
Although it has been hypothesized that lactotrophs are derived
from somatotrophs, possibly through an intermediate somatolactotroph
cell type that coexpresses GH and PRL (17, 18, 19, 20, 21, 22, 23, 24), transcription factors
involved in switching trophic hormone gene expression from GH to PRL
have not been conclusively identified. ER is a candidate factor for
such a role because its ontogeny parallels the ontogeny of PRL
expression (6, 7, 8), and because ER positively regulates PRL
transcription (25, 26, 27, 28, 29, 30, 31, 32, 33). If ER functioned in such a capacity, mice
harboring an ER gene disruption might lack mature lactotrophs that
express only PRL and not GH. To assess the effect of ER gene
disruption on progression of the somatotroph-lactotroph lineage,
pituitary sections from adult ER gene-disrupted female mice were
simultaneously immunostained with antisera directed against both GH and
PRL. Results were visualized using dual indirect immunofluorescence
(Fig. 5). Specification of lactotroph cell phenotype appeared to be
unaffected in the ER gene-disrupted mice based on the readily
observable immunostaining of numerous cells that express PRL but do not
coexpress GH.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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gene-disrupted mice provides genetic evidence for the long-held
hypothesis that a major effect of estrogen in the anterior pituitary
gland is to increase PRL gene expression (25, 26, 27, 28, 29, 30, 31, 32, 33). This may result from
a direct effect on PRL gene transcription and an effect on lactotroph
cell growth. Comparison of PRL mRNA levels in ER gene-disrupted and
ovariectomized wild type mice to intact wild type mice revealed a
greater decrease in PRL mRNA level in the ER gene-disrupted mice
than in ovariectomized wild type mice, suggesting that ER gene
disruption results in a more profound effect on PRL gene expression
than acute loss of estrogenic ligands. In support of a role for
estrogens in lactotroph cell growth (6, 7, 8, 9, 10), immunohistochemical
staining of the pituitary glands of ER gene-disrupted mice with PRL
antisera revealed a modest decrease in lactotroph cell density. Despite
the decrease in PRL mRNA, there was no discernable decrease in
cytoplasmic PRL immunoreactivity in individual lactotroph cells in
sections from ER gene-disrupted mice, in support of a role for ER
in estrogen-stimulated secretion of PRL. The overall decrease in the
size of the anterior pituitary gland noted in the ER gene-disrupted
mice may result from decreased lactotroph cell number and may, in turn,
explain the apparent relative increase in density of the ACTH-,
GSU-, and TSHß-positive cells.
Another potential role for estrogens in the anterior pituitary was
specification of lactotroph cell phenotype (8). Several lines of
independent evidence indicate that the GH-producing somatotrophs and
the PRL-producing lactotrophs are lineally related, with somatotrophs
giving rise to mature lactotrophs (17, 18, 19, 20, 21, 22, 23, 24, 52). Additionally, because
of the parallel ontogeny of ER and PRL gene expression (2), and the
positive effect of estrogen on PRL gene transcription (25, 26, 27, 28, 29, 30, 31, 32, 33) and
lactotroph cell growth (6, 7, 8, 9, 10), it was of interest to examine the
effect of ER gene disruption on progression of the
somatotroph-lactotroph lineage. Dual indirect immunofluorescence
experiments with antisera directed against GH and PRL revealed a large
number of cells staining for PRL, but not GH, in the ER
gene-disrupted mice, indicating that ER is not required for
specification of lactotroph cell phenotype as the
somatotroph-lactotroph lineage progresses.
Increased gonadotropin hormone mRNA levels in ER gene-disrupted mice
have provided support for previous findings indicating that estrogens
suppress synthesis of GSU, LHß, and FSHß subunit mRNAs (36, 37, 38, 39, 40, 41, 42, 43, 44).
Furthermore, when compared to wild type mice, an increase of similar
magnitude in LHß and FSHß mRNA levels was observed in ER
gene-disrupted and ovariectomized wild type mice, suggesting that ER
gene disruption produced the same result as acute loss of estrogenic
ligands. Immunohistochemical staining of the anterior pituitaries of
ER gene-disrupted mice with LHß and FSHß antisera revealed no
change in gonadotroph cell density, but did show a notable decrease in
LHß cytoplasmic immunoreactivity, compatible with a possible
posttranscriptional role for ER.
ER gene-disrupted mice are a valuable model for the study of
estrogen insensitivity in the anterior pituitary gland, as demonstrated
by the profound effects on PRL and gonadotropin gene expression
documented in the ER gene-disrupted mice. The more modest effect on
lactotroph cell growth observed in the ER gene-disrupted mice could
reflect limited biological dependence of lactotroph cell growth on
ER, expression of variant ER transcripts in the ER
gene-disrupted mice, or a possible role for the recently discovered
novel ER, ERß (53, 54, 55). ERß mRNA was not detected, however, by
RNase protection assay of pituitaries from either wild type or ER
gene-disrupted mice, diminishing the likelihood that ERß mediates
estrogen effects in the pituitary (J. Couse and K. Korach, unpublished
data). RNase protection assays with a probe to the ligand-binding
domain of ER, in contrast, detected 10–20% of wild type levels of
ER mRNA in pituitaries from ER gene-disrupted mice (J. Couse and
K. Korach, unpublished data). It has not been proven whether this ER
mRNA represents a variant transcript, such as the E1 transcript
identified in the uterus of ER gene-disrupted mice (47), or the
estrogen-inducible female- and tissue-specific transcripts reported in
the pituitary of the rat (56). In the uterus of the ER
gene-disrupted mice, however, despite the presence of low levels of the
E1 variant transcript, there was no increase of known uterine markers
of estrogen action in response to treatment with estrogen, indicating
that the presence of the E1 transcript did not result in any
biologically significant response to estrogen in this organ (47). In
the pituitary, given the pronounced effect of ER gene disruption on
PRL and gonadotropin gene expression, it seems likely that the more
modest effect on lactotroph cell density may reflect a limited
requirement for ER in normal lactotroph cell growth.
In summary, these genetic data argue that the major effects of ER in
the anterior pituitary gland are in regulation of PRL and gonadotropin
gene expression. The data also suggest a limited role for ER in
lactotroph cell growth and possible involvement of ER in PRL and LH
secretion, but no requirement for ER in specification of the
lactotroph cell phenotype.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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) mice. Pituitaries were
excised and frozen on dry ice, then lysed in Solution D (4
M guanidine isothiocyanate, 25 mM sodium
citrate, pH 7.0, 0.5% sarcosyl, and 0.1 M
2-mercaptoethanol) in a volume of 0.5 ml per pituitary. Sodium acetate,
pH 4.0, was added to 0.2 M final concentration, and the
mixture was extracted with an equal volume of water-saturated phenol
and 0.2 volume of chloroform. The aqueous phase was precipitated with
an equal volume of isopropanol, resuspended in 15% of the original
volume of Solution D, and precipitated again with an equal volume of
isopropanol. The precipitate was washed twice with 75% ethanol and
resuspended in water. The RNA was size fractionated on 1.1%
formaldehyde/1.2% agarose gels, transferred to nylon membranes, and
hybridized overnight at 65 C to DNA probes random-primed-labeled with
Klenow fragment and 32P to a specific activity of
109 cpm/µg. The membranes were washed in
0.3XxNaCl-sodium citrate (SSC) for 45 min at 65 C and exposed to x-ray
film. After x-ray film development, the blots were stripped and
rehybridized with a 32P-labeled ß-actin DNA probe. For
quantification, phosphor screens were exposed to the blots, and the
imaged signals for trophic hormone mRNAs were normalized to the
ß-actin signal.
Immunohistochemical Analysis
Mice were perfused transcardially with 20 ml PBS followed
by 30 ml 10% formalin. Pituitaries were excised, postfixed in
ethanol-37% formaldehyde-H20 water (6:1:3) for 1 h at
room temperature, washed three times in 70% ethanol, and stored in
70% ethanol at 4 C. Pituitaries were dehydrated in isopropanol and
toluene and embedded in paraffin. Five-micrometer thick sections were
cut, mounted, and rehydrated in toluene and ethanol. All further steps
were carried out in a solution of PBS and 0.05% TritonX-100. Sections
were blocked with 10% normal goat serum and immunostained with
polyclonal antisera for 1 h at room temperature. Antisera from the
National Hormone and Pituitary Program (NIDDK, Rockville, MD) were
directed against rat TSHß (AFP-1274789) used at a dilution of
1:10,000, rat LHß (AFP-2223879OGPOLHB) used at 1:12,500, and human
FSHß (AFP-891891) used at 1:250. Antiserum against human ACTH (Sigma
Chemical Co., St. Louis, MO) was used at 1:1000. Antisera against human
GH and human PRL (DAKO, Santa Barbara, CA) were used at 1:200.
Secondary antibodies coupled to horseradish peroxidase and directed
against guinea pig (DAKO) or rabbit (Amersham, Arlington Heights, IL)
were used at 1:100. Diaminobenzidine was the chromogen supplied as a
diaminobenzidine/metal concentrate mixed with stable peroxidase
substrate buffer (Pierce, Rockford, IL). Sections were counterstained
with methyl green. All comparative immunostaining data are derived from
ER gene-disrupted and wild type mouse pituitary sections mounted on
the same slides to ensure uniformity of processing.
Antisera directed against rat GH from the National Hormone and Pituitary Program (AFP 411S) was used at a dilution of 1:3000 and detected with secondary antibody coupled to rhodamine (Cappel, Durham, NC) used at 1:200. Antisera directed against human PRL (Vector, Burlingame, CA) was used at a dilution of 1:250 and detected with secondary antibody coupled to fluorescein (American Qualex, San Clemente, CA) used at 1:100.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Received for publication February 26, 1997. Accepted for publication March 24, 1997.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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-subunit gene
despite the absence of a high affinity binding site for estrogen
receptor. Mol Endocrinol 5:725–733[Abstract]
T3–1 cells. Mol Cell Endocrinol 87:95–103[CrossRef][Medline]
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