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Departments of Obstetrics & Gynecology (J.T., Sa.K.D.) and Molecular & Integrative Physiology (B.C.P., Su.K.D., Sa.K.D.), Ralph L. Smith Research Center, University of Kansas Medical Center, Kansas City, Kansas 66160-7338
Address all correspondence and requests for reprints to: S. K. Das, Departments of Obstetrics & Gynecology and Molecular & Integrative Physiology, MRRC 37/3004, University of Kansas Medical Center, 39th and Rainbow Boulevard, Kansas City, Kansas 66160-7338. E-mail: sdas{at}kumc.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and ER-ß) and progesterone receptor (PR)
in the periimplantation mouse uterus (days 1–8). ER- messenger RNA
(mRNA) was detected at much higher levels in the periimplantation
uterus compared with that of ER-ß mRNA, the levels of which were very
low in all uterine cells during this period. Results of in
situ hybridization demonstrated expression of ER- mRNA
primarily in the luminal and glandular epithelia on days 1 and 2 of
pregnancy. On days 3 and 4, the accumulation was localized primarily in
stromal cells in addition to its presence in the epithelium. Following
implantation on day 5, the accumulation of this mRNA was more condensed
in the luminal and glandular epithelia, but declined in the subluminal
epithelial stroma at the sites of implanting embryos. On days 6–8, the
accumulation of ER- mRNA was primarily localized in the secondary
decidual zone (SDZ) with more intense localization in the subepithelial
cells at the mesometrial pole. In contrast, signals were very low to
undetectable in the primary decidual zone (PDZ), and no signals were
detected in implanting embryos. The undifferentiated stroma underneath
the myometrium also showed positive signals. The immunolocalization of
ER- protein correlated with the mRNA localization. Western blot
analysis showed down-regulation of ER- in day 8 decidual cell
extracts consistent with the down-regulation of ER- mRNA in decidual
cells immediately surrounding the embryo on this day. The expression
pattern of PR was also dynamic in the periimplantation uterus. On day
1, the accumulation of PR mRNA was very low to undetectable, whereas
only a modest level of accumulation in the epithelium was noted on day
2. On days 3 and 4, the accumulation of this mRNA was detected in both
the epithelium and stroma. In contrast, the expression was restricted
only to the stroma with increased signals at the sites of implantation
on day 5. On days 6–8, PR mRNA accumulation increased dramatically
throughout the deciduum. The localization of immunoreactive PR
correlated with the mRNA distribution in the periimplantation uterus.
Taken together, the results demonstrate that the expression of ER-,
ER-ß, and PR is differentially regulated in the periimplantation
mouse uterus. This compartmentalized expression of ER and PR provides
information regarding the sites of coordinated effects of estrogen and
progesterone in the preparation of the uterus for implantation and
decidualization during early pregnancy. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The mechanism(s) by which estrogen initiates implantation in the
P4-primed uterus is not clearly understood. It is thought
that the estrogen and/or P4-mediated events are
accomplished by the expression of a unique set of genes in the uterus.
While female sex steroid hormones directly regulate several genes
including vitellogenin, PRL, uteroglobin, ovalbumin, progesterone
receptor, and lactoferrin in target cells because of the presence of
the steroid-responsive elements in their promoter sequences (reviewed
in Ref. 7), these steroids also modulate the expression of several
growth factors and their receptors in the uterus in a spatiotemporal
manner (8, 9, 10, 11, 12, 13, 14, 15). Steroid hormone actions in target cells are normally
mediated by binding to nuclear receptors, which are ligand-inducible
transcription factors. These transcription factors modulate the
expression of their target genes upon binding to the appropriate
ligands (16, 17, 18, 19). Many of the known physiological actions of estrogens
are considered to be mediated within the target cells primarily by two
nuclear estrogen receptors (ER), ER-, and ER-ß. Molecular analysis
of these two receptors revealed that they share approximately 95% and
55% homology in the DNA binding domain and the hormone binding domain,
respectively. In contrast, the sequence dissimilarity in the
transactivation domains (AF-1 and AF-2) has been suspected for
differential gene activation by these two receptors (reviewed in Ref.
20). Both of these receptors exhibit high affinity binding to estradiol
in the same estrogen response element (ERE) (21, 22). Furthermore,
because these receptor subtypes can form heterodimers in
vitro (23), it is suggested that they can also act together to
regulate gene transcription. The relative distribution and expression
of these receptor subtypes vary considerably within tissue- or
cell-types. For example, ER- has a broad spectrum of expression,
whereas ER-ß shows restricted pattern of expression with high levels
in the ovary, prostate, lung, epididymis, and hypothalamus (21, 24).
However, the biological significance of these differential expression
largely remains undefined. The disruption of ER- gene causes
infertility and defects in the reproductive tract and gonads in
addition to many other abnormalities including behavior and breast
development in females (25, 26, 27). Targeting of the ER-ß gene in the
mouse has revealed a role for ER-ß in ovulation efficiency. However,
this gene is not required for fertility, lactation, or sexual
differentiation (28).
Traditionally P4 is considered as the hormone of pregnancy.
During early pregnancy, this hormone coordinates a series of complex
events that ultimately leads to the synchronized development of the
embryo and differentiation of uterus for implantation. P4
acts through progesterone receptor (PR), a complex binding protein
composed of two isoforms, termed PRA and PRB
(29), originating from a single gene (30, 31). PRA lacks
164 amino acids from the N-terminal region of the full-length receptor,
PRB (32). The relationship between the two isoforms and
their biological activity still remain unclear. The consensus is that
PR is induced by estrogen via the ER. Thus, many of the effects of
P4 may be attributed to the combined effects of estrogen
and P4. However, recent studies demonstrate that
P4 is essential for the induction of uterine
decidualization because this process fails to occur in PR (-/-) mouse
uteri (33). In contrast, ER- (-/-) mouse uteri exhibit
decidualization only in the presence of P4 (34, 35). These
results suggested that estrogenic influence via ER- is minimal for
the induction of decidualization process. Thus, although various
complex uterine responses to ovarian steroids are mediated by
differential effects of these steroids, to our knowledge no
comprehensive information regarding spatiotemporal expression of these
receptors in the mouse uterus during the periimplantation period is
available. This basic information is important to ascertain whether
implantation and decidualization defects resulting from targeting of
several genes are due to altered uterine responsiveness to steroids
and/or altered uterine expression of ER and/or PR. Thus, we examined
spatiotemporal expression of ER-, ER-ß, and PR in the
periimplantation mouse uterus. The results clearly demonstrate that
these receptors are differentially expressed in the uterus in a
spatiotemporal manner.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Hybridization probes
All of the complementary DNAs (cDNAs) used were specific to the
mouse. A 342-bp cDNA fragment (nt 659-1000, GenBank Accession No.
M38651) of ER- was obtained by RT-PCR. For RT reaction, day 4
pregnant mouse uterine total RNA was used. The RT-PCR derived fragment
was subcloned into pCR-Script (SK)+ vector, and the
identity of the clone was confirmed by nucleotide sequencing. The
subcloning and vectors for mouse ER-ß, PR, and the ribosomal protein
L7 (rpL7) have been previously described (10, 35, 36). For Northern
blot hybridization, antisense 32P-labeled complementary RNA
(cRNA) probes were generated using SP6 polymerase. For in
situ hybridization, sense and antisense 35S-labeled
cRNA probes were generated using appropriate RNA polymerases. The
probes had specific activities of 2 x 109
dpm/µg.
Northern blot hybridization
Total RNAs were extracted from whole uteri pooled from 7–10
mice on the indicated day of pregnancy by a modified guanidine
thiocyanate procedure (37, 38). Polyadenylated [poly
(A+)] RNAs were isolated from total RNAs by
oligo(dT)-cellulose column chromatography (39). Poly (A+)
RNA (2.0 µg) was denatured, separated by formaldehyde-agarose gel
electrophoresis, and transferred to nylon membranes. RNA was
cross-linked to the membranes by UV irradiation (Spectrolinker,
XL-1500; Spectronics Corp., Westbury, NY) and the blots were
prehybridized, hybridized, and washed as previously described by us (9, 38). Except for ER-ß, the blots were hybridized and washed under
stringent condition as described by us (40). The stripping of
hybridized probe for subsequent rehybridization was achieved as
described (9, 14). The hybrids were detected by autoradiography (38)
and the autoradiographic exposure times are indicated in the figure
legends.
In situ hybridization
In situ hybridization was performed as previously
described (8, 10, 11). In brief, frozen sectioned were mounted onto
poly-L-lysine coated slides and fixed in 4%
paraformaldehyde in PBS for 15 min at 4 C. Sections were prehybridized
followed by hybridization with 35S-labeled antisense or
sense cRNA probes for 4 h at 45 C. After hybridization and
washing, the sections were incubated with RNase-A (20 µg/ml) at 37 C
for 20 min. RNase-A resistant hybrids were detected by autoradiography
using Kodak NTB-2 liquid emulsion (Eastman Kodak Co., Rochester, NY). The slides were poststained with
hematoxylin and eosin. The reddish brown grains indicate the sites of
messenger RNA (mRNA) accumulation. This color shade is the result of
lateral light scattering from the eosin staining under dark-field
microscopy. Sections hybridized with the sense probes served as
negative controls.
Antibodies
The affinity-purified rabbit polyclonal antibody, C1355 for rat
ER- isoform was obtained from Dr. M. A. Shupnik, University of
Virginia Medical Center (Charlottesville, VA). This antibody was raised
against a peptide for the last 14 amino acids in the C-terminal end of
rat ER- (41). Mouse monoclonal antihuman PR was purchased from
Zymed Laboratories, Inc. (catalog no. ZS08–0172;
Zymed Laboratories, Inc., San Francisco, CA). This
antibody was developed against a peptide in the N-terminal proline-rich
region of human PR. Both ER- and PR antibodies cross-react with
corresponding mouse proteins. These antibodies were used for protein
analysis using either immunostaing and/or Western blotting
experiments.
Immunohistochemical staining
The localization of nuclear ER- and PR was achieved by
immunohistochemistry. Small pieces of mouse uteri recovered on days 4,
5, and 8 of pregnancy were fixed in 10% neutral buffered formalin for
24 h at 4 C followed by dehydration in ascending grades of
ethanol, cleared in xylene, and embedded in paraffin. Paraffin sections
(6 µm) where placed onto poly-L-lysine-coated slides.
Sections were deparaffinized in xylene and hydrated in descending
grades of ethanol. After washing 2 times (5 min each) in PBS, slides
were placed in a plastic Coplin jar filled with 10 mM
citrate buffer (pH 6.0), and irradiated for 8 min in microwave oven
(antigen retrieval) followed by cooling to room temperature. Sections
were washed twice in PBS. Nonspecific reaction was blocked by
incubating the sections in 10% nonimmune goat serum (for ER-) or
rabbit serum (for PR) for 10 min. Sections were incubated with ER-
primary antibody (1:10,000 in PBS) and PR antibody (ready-to-use) in a
humidified chamber at 4 C for 18 h. After incubation, sections
were washed twice in PBS followed by incubation in secondary
antibodies, goat antirabbit (for ER-), or rabbit antimouse (for PR)
for 10 min. Sections were washed thoroughly in PBS and incubated with
0.23% periodic acid for 30 sec to block endogenous peroxidase
activity. Sections were washed again in PBS and stained using a
Zymed Laboratories, Inc. Histostain-SP kit (Zymed Laboratories, Inc. San Francisco, CA). Red deposits indicted the
sites of positive immunostaining.
Western blot analysis
Proteins were extracted from the whole uterus on day 4, and from
the separated decidua and the uterus minus decidua on day 8 of
pregnancy by homogenization in buffer containing 50 mM Tris
(pH 7.4), 1 mM EDTA, 150 mM NaCl and proteinase
inhibitors (1 µg/ml phenylmethylsulfonyl fluoride, 10 µg/ml
aprotinin, and 1 µg/ml leupeptin). The homogenates were centrifuged
at 2000 x g for 15 min at 4 C. The supernatants were
separated and their protein concentrations were measured. The
supernatants (50 µg protein) were boiled for 5 min in SDS sample
buffer [0.06 M Tris-HCl (pH 6.8), 2% SDS, 10% glycerol,
0.7 M ß-mercaptoethanol] containing 0.01% bromophenol
blue dye. After centrifugation, the samples were run on 7.5% SDS-PAGE
gels under reducing condition and transferred onto nitrocellulose
membranes. The membranes were blocked with 5% carnation milk in TBS
[10 mM Tris-HCl (pH 8.0) and 150 mM NaCl]
plus 0.05% Tween-20 for overnight at 4 C and then incubated in 5%
milk containing antibodies (1:7500) to ER- for overnight at 4 C or
2 h at room temperature. After incubation, membranes were washed
three times (10 min each) with 5% milk, incubated with goat antirabbit
IgG conjugated with horseradish peroxidase (1:5000) in 5% milk for
1 h, and washed 3 times (5 min each) in TBS. The bands were
detected by ECL kit (Amersham Pharmacia Biotech, Arlington
Heights, IL).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, ER-ß, and PR mRNAs in the
periimplantation mouse uterus, ER-ß, and PR mRNAs in the
uterus on days 1–8 of pregnancy were examined by Northern blot
hybridization using mouse-specific cRNA probes (Fig. 1
, a and b). Consistent with the previous
report (22), a single transcript (
6.0 kb) for ER- mRNA was
detected at higher abundance in the uterus on days 1–8 of pregnancy,
whereas the abundance of this mRNA was very low in the adult mouse
ovary (Fig. 1a). In general, the levels of ER- mRNA did not show
much variation in the uterus during this period. In contrast, the
abundance for ER-ß mRNA in the periimplantation uterus was extremely
low, although some expression was noted on days 2–4 and days 6–7. As
detected before for ER-ß (22), three major transcripts (9.5, 4.6,
and 3.0 kb) and a minor transcript (7.2 kb) were detected in the
ovary, whereas three transcripts (7.2, 6.0, and 4.6 kb) were
detected in the pregnant uterus (Fig. 1a). Consistent with previous
reports (22, 35, 42), ER-ß mRNA expression was high in the ovary
(Fig. 1b). Consistent with our previous observation (36), four
different transcripts (8.5, 6.5, 4.0, and 3.2 kb) of PR were
detected in the periimplantation uterus. The analysis of the levels of
these transcripts revealed that the expression was low on days 1 and 2
followed by substantial increases on days 3–5. The levels of
expression declined on day 6, but again increased on days 7 and 8. The
integrity and loading of RNA samples were examined by rehybridizing the
same blots to a mouse rpL7 cRNA probe.
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, ER-ß, and PR mRNAs in the
periimplantation mouse uterus, ER-ß, and PR
mRNAs during the periimplantation period, in situ
hybridization was performed (Figs. 2, 3, and 4,
respectively). On days 1 and 2, distinct
autoradiographic signals of ER- mRNA were evident primarily in the
luminal and glandular epithelia (Fig. 2, a–d). On day 3, accumulation
of this mRNA was noted in the subluminal stromal cells in addition to
its localization in epithelial cells (Fig. 2, e and f). On day 4, the
pattern of accumulation was similar to that of day 3, but the signals
were more widespread and intense (Fig. 2, g and h). The expression
pattern did not alter at the site of blastocyst before implantation on
this day. Following implantation on day 5, the autoradiographic signals
increased further in the glandular and luminal epithelia, and in the
subluminal epithelial stroma at the mesometrial pole. However, the
signals were less intense in the decidualizing stroma at the site of
implantation at the antimesometrial pole (Fig. 2, i and j). On days
6–8, autoradiographic signals were primarily detected in the secondary
decidual zone (sdz) and signals were more intense at the mesometrial
pole, the presumptive site of placentation (Fig. 2, k–p). ER- mRNA
accumulation was very low or undetectable at the primary decidual zone
(pdz) immediately surrounding the implanting embryo. Furthermore, the
undifferentiated stroma (us) just above the myometrium showed positive
signals during days 7 and 8 of pregnancy (Fig. 2, m–p).
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mRNA was very low in the ovary (Fig. 3a
),
although epithelial cells in the oviduct lumen attached to the ovarian
sections showed strong signals for ER- mRNA (Fig. 3a). On the
contrary, as observed previously (22, 35, 42), the accumulation of
ER-ß mRNA was intense in ovarian follicles at all stages of
development (Fig. 3b). However, ER-ß mRNA was not detected in
oviductal cells (Fig. 3b). Consistent with previous findings by us and
others (24, 35), uterine expression of ER-ß mRNA in general was
extremely low during early pregnancy compared with ER- mRNA (see
Fig. 3, c and d, vs. Fig. 2).
The accumulation of PR mRNA was very low to undetectable on day 1 of
pregnancy followed by low level accumulation in the epithelium on day 2
(Fig. 4, a and b). In contrast, the expression of PR mRNA was
significantly up-regulated in both the epithelium and the subepithelial
stroma on days 3 and 4 (Fig. 4, c and d). The presence of blastocysts
in the uterus before the onset of implantation did not alter the
expression pattern (Fig. 4d). After implantation on day 5, the
accumulation of mRNA was no longer detectable in the luminal
epithelium, but was strikingly up-regulated in the subepithelial stroma
at the site of implantation (Fig. 4e). With the progression of
implantation on days 6 and 7 of pregnancy, the accumulation of PR mRNA
increased dramatically throughout the decidual bed both at the
mesometrial and the antimesometrial poles (Fig. 4, f–h). The
expression pattern of PR mRNA on day 8 was similar to that of day 7
(data not shown).
Analysis of immunoreactive ER- and PR in the periimplantation
mouse uterus
To examine the cellular distribution of nuclear ER- and PR in
the pregnant mouse uterus, immunohistochemistry was performed during
the preimplantation (day 4 morning) and postimplantation (days 5 and 8)
period. Consistent with in situ hybridization results,
immunoreactive ER- protein was detected in same uterine cell types
that expressed ER- mRNA (Fig. 5). On
day 4, accumulation was high in the glandular epithelium (Fig. 5, a and
b). The luminal epithelium and the subepithelial stroma also showed
distinct, albeit at low levels, nuclear staining. On day 5, the high
levels of immunostaining persisted in the glandular epithelium. In
addition, mostly the luminal epithelium and subluminal epithelial
stroma at the mesometrial pole were positive for ER- (Fig. 5, c and
d). On day 8, ER- was detected primarily in stromal cells adjacent
to the luminal epithelium at the mesometrial pole, and also in the
undifferentiated stromal cells underneath the myometrium both at the
mesometrial and antimesometrial poles (Fig. 5, e–g). Furthermore, some
glands situated within the undifferentiated stroma remained strongly
positive for ER- (Fig. 5f). Immunostaining was not detected in the
implanting embryo or in decidualizing stromal cells immediately
surrounding the embryo (Fig. 5g). With respect to PR, nuclear
immunostaining was detected predominantly in the luminal epithelium and
in the subepithelial stroma on day 4 of pregnancy (Fig. 6, a and b). In contrast to ER-,
nuclear accumulation of PR on this day in the gland was below the level
of detection (Fig. 6, a and b). On day 5, immunostaining was primarily
restricted to the subepithelial stroma at the sites of implantation
(Fig. 6, c and d). The luminal and glandular epithelia were devoid of
immunostaining. On day 8, immunoreactive PR was distributed throughout
the decidual bed both at the mesometrial and the antimesometrial poles
(Fig. 6, e and f). The staining for PR was absent in the embryo proper.
However, the positive staining for PR was detected in the region of the
extraembryonic endoderm (xen) (Fig. 6f).
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were performed to
determine the size and the levels of accumulation of this protein
during pregnancy in the whole uterus on day 4 and the separated decidua
and uterus minus decidua on day 8 of pregnancy (Fig. 7). As detected before (43), the same
polyclonal antibody detected a major band (66 kDa) for full-length
ER- in uterine tissues (Fig. 7a). However, a minor band (50 kDa)
was also detected in the uterus on day 8 of pregnancy. The identity of
this minor band is not known. The densitometric quantitation of the
major band revealed that the expression of ER- was down-regulated in
the decidua on day 8 of pregnancy (Fig. 6b).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, ER-ß, and PR by
autoradiographic ligand binding and immunohistochemistry has been
demonstrated in the uterus of various species (44, 45, 46, 47, 48, 49). However,
interactions between ER and PR with respect to ovarian steroid hormone
effects in uterine biology during early pregnancy are poorly
understood. This investigation demonstrates uterine expression of
ER-, ER-ß, and PR with respect to periimplantation events in the
mouse. Although ovarian steroids primarily direct uterine cell
proliferation and differentiation in a spatiotemporal manner during the
periimplantation period, the molecular mechanisms involved in these
processes are poorly understood. In the mouse, implantation occurs at
2300 h on day 4 of pregnancy. An extremely low level of estrogen
is required to initiate this process in a P4-primed uterus,
suggesting that estrogen mediated effects in the uterus are locally
amplified by various growth factors. This suggestion is consistent with
the temporal and cell-specific expression of several growth factors and
their receptors in the uterus and/or embryo at the time of implantation
(reviewed in Refs. 10, 12). The expression of ER- in the uterine
epithelium on day 1 of pregnancy under the influence of preovulatory
estrogen is correlated with epithelial cell proliferation, whereas
stromal cell expression of both ER- and PR under the influence of
rising P4 and preimplantation ovarian estrogen secretion on
day 4 is associated with stromal cell proliferation. In contrast,
expression of ER- and PR in luminal epithelial cells is correlated
with cessation of their proliferation because differentiation of these
cells are essential for interactions with blastocyst trophectoderm for
implantation.
Cross-tissue recombination of the uterine epithelium and stroma between
the wild-type and PR null mice suggests that stromal cell PR is
important in mediating the inhibitory effects of P4 on
epithelial cell proliferation (50). A similar approach using the
wild-type and ER- mutant mice proposes that estrogen positively
controls epithelial cell proliferation via stromal cell ER- in a
paracrine manner (51). Our observation of differential expression of
ER- and PR in the luminal and glandular epithelial cells on day 4 of
pregnancy suggests that these two epithelial cell types behave
differently as potential targets to P4 and estrogen with
respect to mesenchymal interactions for preparation of the uterus to
implantation (Fig. 5, a and b, vs. Fig. 6, a and b). This is
consistent with the expression of amphiregulin (a P4
responsive gene) in both the luminal and glandular epithelia and
leukemia inhibitory factor (estrogen-regulated gene) primarily in the
glandular epithelium on day 4 of pregnancy (9, 52, 53). On day 5, the
absence of epithelial PR with persistent ER- may be responsible for
down-regulation of epithelial expression of amphiregulin because
estrogen antagonizes P4 induction of amphiregulin (9).
The general consensus is that estrogen induces progesterone receptors
(PR) in the uterus (36, 54). Furthermore, studies in primates and cats
have demonstrated that uterine expression of ER- and PR is increased
by estrogen, whereas P4 reduces their expression (55, 56).
In addition, it has recently been demonstrated that estrogen has dual
effects on the expression of PR, i.e. it decreases PR levels
in the luminal epithelium but increases the levels of PR in the stroma
and myometrium (57). The significance of our present observation of
discoordinate expression of ER- and PR in the luminal epithelium on
day 1 of pregnancy under the influence of preovulatory estrogen and
P4 is not clear. On this day, several estrogen-regulated
genes have been shown to be induced (13, 52, 53, 58, 59), whereas
progesterone-regulated genes are not inducible, probably because of the
absence of PR. Thus, the heightened expression of ER-, but not PR,
in the epithelium suggests a differential regulation of PR.
Furthermore, up-regulation of PR, as opposed to down-regulation of
ER-, in the decidua on days 7 and 8 of pregnancy may suggest that PR
could be regulated by some non-ER-mediated pathway. This suggestion is
in agreement with the recent demonstration of induction of
decidualization in ER- null mice with up-regulation of uterine PR
(35). The down-regulation of the ER-, together with very low levels
ER-ß expression, in the deciduum also suggests that ERs have limited
functions in this process. This is consistent with the observation that
progesterone, but not estrogen, is an absolute requirement for
sustained decidualization in the rodent, although estrogen is essential
for the initiation of the implantation process (reviewed in Ref. 6). In
contrast, low levels of ER- mRNA in the SDZ at the antimesometrial
pole on day 8 are associated with diminishing cell proliferation.
Adequate levels of P4 and stromal expression of PR are necessary for optimal decidualization (60, 61). It has recently been implicated that Hoxa-10 is involved in stromal cell responsiveness to P4 (62). Hoxa-10 is expressed in the stroma on day 4 and in decidualizing stroma on day 5 of pregnancy, suggesting that this gene is important for stromal cell proliferation and subsequent decidualization. Indeed, the null mutation of this gene causes decidualization defect in the mouse (63, 64). Recent results also show that P4-dependent stromal cell proliferation is compromised in Hoxa-10 (-/-) uteri, whereas E2-dependent epithelial cell proliferation is normal (62). However, reduced stromal responsiveness to P4 and decidualization defect in Hoxa-10 (-/-) mice are not the result of reduced uterine expression of PR, suggesting that Hoxa-10’s role in uterine functions is downstream of PR. P4 effects via PR is an absolute requirement for sustained decidualization in the rodent (reviewed in Ref. 6) because this response is prevented by blocking P4 actions by neutralizing antibody or PR antagonists (60, 65, 66). The failure of decidualization in PR null mice is also consistent with these observations (33).
In conclusion, the results of this investigation have demonstrated a
differential expression pattern of nuclear ER-, ER-ß, and PR in
the mouse uterus during early pregnancy and provide insights to our
understanding regarding the roles of these receptors in uterine biology
during implantation and decidualization.
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Footnotes |
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Received May 24, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and ß. Endocrinology 138:863–870. Mol Endocrinol 11:1486–1496 (ER) and estrogen receptor-ß (ERß) messenger
ribonucleic acid in the wild-type and ER-knockout mouse.
Endocrinology 138:4613–4621. Proc Natl Acad Sci USA 95:15677–15682 knockout mouse uterus. Proc Natl Acad Sci
USA 96:3646–3651 deficient
mice. Endocrinology 140:2704–2710 in the
mouse uterus during the periimplantation period. Biol Reprod 45:365–372[Abstract]
and
ß in the rat pituitary gland. Endocrinology 139:3976–3983 and ß in rat ovary and
uterus. J Mol Endocrinol 22:37–44[Abstract]
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J.-W. Jeong, K. Y. Lee, S. J. Han, B. J. Aronow, J. P. Lydon, B. W. O'Malley, and F. J. DeMayo The p160 Steroid Receptor Coactivator 2, SRC-2, Regulates Murine Endometrial Function and Regulates Progesterone-Independent and -Dependent Gene Expression Endocrinology, September 1, 2007; 148(9): 4238 - 4250. [Abstract] [Full Text] [PDF]
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 R. L. Kelley, K. L. Kind, M. Lane, R. L. Robker, J. G. Thompson, and L. J. Edwards Recombinant human follicle-stimulating hormone alters maternal ovarian hormone concentrations and the uterus and perturbs fetal development in mice Am J Physiol Endocrinol Metab, October 1, 2006; 291(4): E761 - E770. [Abstract] [Full Text] [PDF]
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A. Khatua, X. Wang, T. Ding, Q. Zhang, J. Reese, F. J. DeMayo, and B. C. Paria Indian Hedgehog, But Not Histidine Decarboxylase or Amphiregulin, Is a Progesterone-Regulated Uterine Gene in Hamsters Endocrinology, September 1, 2006; 147(9): 4079 - 4092. [Abstract] [Full Text] [PDF]
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S. Ray, X. Hou, H.-E. Zhou, H. Wang, and S. K. Das Bip Is a Molecular Link between the Phase I and Phase II Estrogenic Responses in Uterus Mol. Endocrinol., August 1, 2006; 20(8): 1825 - 1837. [Abstract] [Full Text] [PDF]
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 J-W Jeong, K Y Lee, J P Lydon, and F J DeMayo Steroid hormone regulation of Clca3 expression in the murine uterus. J. Endocrinol., June 1, 2006; 189(3): 473 - 484. [Abstract] [Full Text] [PDF]
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M. C. Velarde, Y. Geng, R. R. Eason, F. A. Simmen, and R. C.M. Simmen Null Mutation of Kruppel-Like Factor9/Basic Transcription Element Binding Protein-1 Alters Peri-Implantation Uterine Development in Mice Biol Reprod, September 1, 2005; 73(3): 472 - 481. [Abstract] [Full Text] [PDF]
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 H. Wang, S. Tranguch, H. Xie, G. Hanley, S. K. Das, and S. K. Dey Variation in commercial rodent diets induces disparate molecular and physiological changes in the mouse uterus PNAS, July 12, 2005; 102(28): 9960 - 9965. [Abstract] [Full Text] [PDF]
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J Varayoud, J G Ramos, L Monje, V Bosquiazzo, M Munoz-de-Toro, and E H Luque The estrogen receptor {alpha} {Sigma}3 mRNA splicing variant is differentially regulated by estrogen and progesterone in the rat uterus J. Endocrinol., July 1, 2005; 186(1): 51 - 60. [Abstract] [Full Text] [PDF]
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 L.-J. Xiao, J.-X. Yuan, Y.-C. Li, R. Wang, Z.-Y. Hu, and Y.-X. Liu Extracellular Ca2+-sensing receptor expression and hormonal regulation in rat uterus during the peri-implantation period Reproduction, June 1, 2005; 129(6): 779 - 788. [Abstract] [Full Text] [PDF]
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G. Nie, Y. Li, M. Wang, Y. X. Liu, J. K. Findlay, and L. A. Salamonsen Inhibiting Uterine PC6 Blocks Embryo Implantation: An Obligatory Role for a Proprotein Convertase in Fertility Biol Reprod, April 1, 2005; 72(4): 1029 - 1036. [Abstract] [Full Text] [PDF]
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T. Daikoku, S. Tranguch, D. B. Friedman, S. K. Das, D. F. Smith, and S. K. Dey Proteomic Analysis Identifies Immunophilin FK506 Binding Protein 4 (FKBP52) as a Downstream Target of Hoxa10 in the Periimplantation Mouse Uterus Mol. Endocrinol., March 1, 2005; 19(3): 683 - 697. [Abstract] [Full Text] [PDF]
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H. He, D. J. McCartney, Q. Wei, S. Esadeg, J. Zhang, R. A. Foster, M. A. Hayes, C. Tayade, F. Van Leuven, and B. A. Croy Characterization of a Murine Alpha 2 Macroglobulin Gene Expressed in Reproductive and Cardiovascular Tissue Biol Reprod, February 1, 2005; 72(2): 266 - 275. [Abstract] [Full Text] [PDF]
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X. Hou, Y. Tan, M. Li, S. K. Dey, and S. K. Das Canonical Wnt Signaling Is Critical to Estrogen-Mediated Uterine Growth Mol. Endocrinol., December 1, 2004; 18(12): 3035 - 3049. [Abstract] [Full Text] [PDF]
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J. R. A. Sherwin, T. C. Freeman, R. J. Stephens, S. Kimber, A. G. Smith, I. Chambers, S. K. Smith, and A. M. Sharkey Identification of Genes Regulated by Leukemia-Inhibitory Factor in the Mouse Uterus at the Time of Implantation Mol. Endocrinol., September 1, 2004; 18(9): 2185 - 2195. [Abstract] [Full Text] [PDF]
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B. Mulac-Jericevic and O. M Conneely Reproductive tissue selective actions of progesterone receptors Reproduction, August 1, 2004; 128(2): 139 - 146. [Abstract] [Full Text] [PDF]
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 R. C. M. Simmen, R. R. Eason, J. R. McQuown, A. L. Linz, T.-J. Kang, L. Chatman Jr., S. R. Till, Y. Fujii-Kuriyama, F. A. Simmen, and S. P. Oh Subfertility, Uterine Hypoplasia, and Partial Progesterone Resistance in Mice Lacking the Kruppel-like Factor 9/Basic Transcription Element-binding Protein-1 (Bteb1) Gene J. Biol. Chem., July 9, 2004; 279(28): 29286 - 29294. [Abstract] [Full Text] [PDF]
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T. E. Spencer, G. A. Johnson, R. C. Burghardt, and F. W. Bazer Progesterone and Placental Hormone Actions on the Uterus: Insights from Domestic Animals Biol Reprod, July 1, 2004; 71(1): 2 - 10. [Abstract] [Full Text] [PDF]
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 S. K. Dey, H. Lim, S. K. Das, J. Reese, B. C. Paria, T. Daikoku, and H. Wang Molecular Cues to Implantation Endocr. Rev., June 1, 2004; 25(3): 341 - 373. [Abstract] [Full Text] [PDF]
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M. H. Melner, N. A. Ducharme, A. R. Brash, V. P. Winfrey, and G. E. Olson Differential Expression of Genes in the Endometrium at Implantation: Upregulation of a Novel Member of the E2 Class of Ubiquitin-Conjugating Enzymes Biol Reprod, February 1, 2004; 70(2): 406 - 414. [Abstract] [Full Text] [PDF]
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R. M. Bigsby, A. Caperell-Grant, N. Berry, K. Nephew, and D. Lubahn Estrogen Induces a Systemic Growth Factor Through an Estrogen Receptor-Alpha-Dependent Mechanism Biol Reprod, January 1, 2004; 70(1): 178 - 183. [Abstract] [Full Text] [PDF]
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D. O. Walterhouse, M. L.G. Lamm, E. Villavicencio, and P. M. Iannaccone Emerging Roles for Hedgehog-Patched-Gli Signal Transduction in Reproduction Biol Reprod, July 1, 2003; 69(1): 8 - 14. [Abstract] [Full Text] [PDF]
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W. Cui, D. Wylie, S. Aslam, A. Dinnyes, T. King, I. Wilmut, and A. J. Clark Telomerase-Immortalized Sheep Fibroblasts Can Be Reprogrammed by Nuclear Transfer to Undergo Early Development Biol Reprod, July 1, 2003; 69(1): 15 - 21. [Abstract] [Full Text] [PDF]
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X.-L. Zhang, D. Zhang, F. J. Michel, J. L. Blum, F. A. Simmen, and R. C. M. Simmen Selective Interactions of Kruppel-like Factor 9/Basic Transcription Element-binding Protein with Progesterone Receptor Isoforms A and B Determine Transcriptional Activity of Progesterone-responsive Genes in Endometrial Epithelial Cells J. Biol. Chem., June 6, 2003; 278(24): 21474 - 21482. [Abstract] [Full Text] [PDF]
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K.B.C. Apparao, M. J. Illera, S. A. Beyler, G. E. Olson, K. G. Osteen, M. H. Corjay, K. Boggess, and B. A. Lessey Regulated Expression of Osteopontin in the Peri-Implantation Rabbit Uterus Biol Reprod, May 1, 2003; 68(5): 1484 - 1490. [Abstract] [Full Text] [PDF]
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N. Baran, P. A. Kelly, and N. Binart Decysin, a New Member of the Metalloproteinase Family, Is Regulated by Prolactin and Steroids During Mouse Pregnancy Biol Reprod, May 1, 2003; 68(5): 1787 - 1792. [Abstract] [Full Text] [PDF]
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T. Daikoku, H. Matsumoto, R. A. Gupta, S. K. Das, M. Gassmann, R. N. DuBois, and S. K. Dey Expression of Hypoxia-inducible Factors in the Peri-implantation Mouse Uterus Is Regulated in a Cell-specific and Ovarian Steroid Hormone-dependent Manner. EVIDENCE FOR DIFFERENTIAL FUNCTION OF HIFs DURING EARLY PREGNANCY J. Biol. Chem., February 21, 2003; 278(9): 7683 - 7691. [Abstract] [Full Text] [PDF]
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Y.-P. Cheon, Q. Li, X. Xu, F. J. DeMayo, I. C. Bagchi, and M. K. Bagchi A Genomic Approach to Identify Novel Progesterone Receptor Regulated Pathways in the Uterus during Implantation Mol. Endocrinol., December 1, 2002; 16(12): 2853 - 2871. [Abstract] [Full Text] [PDF]
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N. Takamoto, B. Zhao, S. Y. Tsai, and F. J. DeMayo Identification of Indian Hedgehog as a Progesterone-Responsive Gene in the Murine Uterus Mol. Endocrinol., October 1, 2002; 16(10): 2338 - 2348. [Abstract] [Full Text] [PDF]
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 C. W. Gregory, E. M. Wilson, K. B. C. Apparao, R. A. Lininger, W. R. Meyer, A. Kowalik, M. A. Fritz, and B. A. Lessey Steroid Receptor Coactivator Expression throughout the Menstrual Cycle in Normal and Abnormal Endometrium J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2960 - 2966. [Abstract] [Full Text] [PDF]
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N. Baran, P. A. Kelly, and N. Binart Characterization of a Prolactin-Regulated Gene in Reproductive Tissues Usingthe Prolactin Receptor Knockout Mouse Model Biol Reprod, April 1, 2002; 66(4): 1210 - 1218. [Abstract] [Full Text] [PDF]
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G. Leonardsson, M. A. Jacobs, R. White, R. Jeffery, R. Poulsom, S. Milligan, and M. Parker Embryo Transfer Experiments and Ovarian Transplantation Identify the Ovary as the Only Site in Which Nuclear Receptor Interacting Protein 1/RIP140 Action Is Crucial for Female Fertility Endocrinology, February 1, 2002; 143(2): 700 - 707. [Abstract] [Full Text] [PDF]
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J.-G. Cheng, J. R. Chen, L. Hernandez, W. G. Alvord, and C. L. Stewart Dual control of LIF expression and LIF receptor function regulate Stat3 activation at the onset of uterine receptivity and embryo implantation PNAS, June 28, 2001; (2001) 151180898. [Abstract] [Full Text] [PDF]
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 M. Maccarrone, H. Valensise, M. Bari, N. Lazzarin, C. Romanini, and A. Finazzi-Agro Progesterone Up-Regulates Anandamide Hydrolase in Human Lymphocytes: Role of Cytokines and Implications for Fertility J. Immunol., June 15, 2001; 166(12): 7183 - 7189. [Abstract] [Full Text] [PDF]
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B. M. Bany and G. A. Schultz Increased Expression of a Novel Heat Shock Protein Transcript in the Mouse Uterus During Decidualization and in Response to Progesterone Biol Reprod, January 1, 2001; 64(1): 284 - 292. [Abstract] [Full Text]
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C. Tessier, S. Deb, A. Prigent-Tessier, S. Ferguson-Gottschall, G. B. Gibori, R. P. C. Shiu, and G. Gibori Estrogen Receptors {alpha} and {beta} in Rat Decidua Cells: Cell-Specific Expression and Differential Regulation by Steroid Hormones and Prolactin Endocrinology, October 1, 2000; 141(10): 3842 - 3851. [Abstract] [Full Text] [PDF]
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H. Song, H. Lim, S. K. Das, B. C. Paria, and S. K. Dey Dysregulation of EGF Family of Growth Factors and COX-2 in the Uterus during the Preattachment and Attachment Reactions of the Blastocyst with the Luminal Epithelium Correlates with Implantation Failure in LIF- Deficient Mice Mol. Endocrinol., August 1, 2000; 14(8): 1147 - 1161. [Abstract] [Full Text]
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 C. Brisken, A. Heineman, T. Chavarria, B. Elenbaas, J. Tan, S. K. Dey, J. A. McMahon, A. P. McMahon, and R. A. Weinberg Essential function of Wnt-4 in mammary gland development downstream of progesterone signaling Genes & Dev., March 15, 2000; 14(6): 650 - 654. [Abstract] [Full Text]
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J.-G. Cheng, J. R. Chen, L. Hernandez, W. G. Alvord, and C. L. Stewart Dual control of LIF expression and LIF receptor function regulate Stat3 activation at the onset of uterine receptivity and embryo implantation PNAS, July 17, 2001; 98(15): 8680 - 8685. [Abstract] [Full Text] [PDF]
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