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Department of Molecular and Integrative Physiology (H.L.,
W-G.M., S.K.D.) Ralph L. Smith Research Center University of
Kansas Medical Center Kansas City, Kansas 66160-7338
Division of Genetics (L.M., R.L.M.) Brigham and Women’s
Hospital and Harvard Medical School Boston, Massachusetts 02115
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ABSTRACT |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Hoxa-10 is one AbdominalB-like homoeobox gene that is located in the Hoxa cluster and expressed in the developing genitourinary tract during mouse embryogenesis (3). Its distinct role in development has been defined by gene targeting experiments (6, 7). Hoxa-10-deficient mice exhibit male and female infertility along with a homeotic transformation of the lumbar vertebrae. Although the proximal uterus of Hoxa-10(-/-) mice shows partial homeosis into an oviduct-like structure, this is not the major cause of infertility in these mice. Hoxa-10 is strongly expressed in the stroma and decidua of the pregnant mouse uterus (6), and decidualization in Hoxa-10(-/-) mice is severely compromised during blastocyst implantation (8), thus reflecting a maternal requirement for Hoxa-10 in the periimplantation uterus. However, the mechanism by which Hoxa-10 regulates uterine stromal cell proliferation and differentiation during decidualization remains unknown. Recent investigations have revealed that Hoxa-10 (9, 10) and other AbdB-like Hoxa genes (9) are regulated by progesterone (P4) in the mouse and human endometrium. Hoxa-10 is induced in the mouse uterine stroma within 4 h of a P4 injection in a protein synthesis-independent fashion, and the up-regulation of Hoxa-10 by P4 is inhibited by the progesterone receptor (PR) antagonist RU-486, suggesting a requirement for PR for this induction (9). These studies imply that Hoxa-10 is a primary steroid hormone-responsive gene and that it is involved in implantation as a direct mediator of P4 actions. The adjacent AbdB gene, Hoxa-11, is also regulated by ovarian steroids in the uterine stroma (9), and Hoxa-11 mutant mice also exhibit female infertility originating from uterine defects similar to those in Hoxa-10(-/-) mice (11, 12).
A precise coordination between the establishment of uterine receptivity
and blastocyst activation is essential to the process of implantation
(13, 14). Ovarian P4 and estrogen play key roles in
implantation and subsequent decidualization. While preovulatory
estrogen secretion induces epithelial cell proliferation on day 1 of
pregnancy, superimposition of estrogen on P4 priming on day
4 directs stromal cell proliferation and epithelial cell
differentiation necessary for implantation in the mouse (15). This
profile of uterine cell proliferation can be mimicked in the
ovariectomized mouse uterus by ovarian steroids. For example, a single
injection of 17ß-estradiol (E2) induces epithelial cell
proliferation, while P4 induces stromal cell proliferation
by 24 h, which is further potentiated by E2 (15).
However, the mechanism by which these steroid hormones regulate uterine
cell-specific proliferation and differentiation is unclear. The initial
attachment reaction of the blastocyst trophectoderm with the luminal
epithelium, which coincides with increased stromal vascular
permeability and occurs around 2200–2300 h on day 4 of pregnancy, is
followed by stromal cell proliferation and differentiation
(decidualization) at the sites of blastocyst apposition (14).
P4 is an absolute requirement for decidualization since
PR-deficient mice fail to exhibit decidualization, while estrogen
receptor-
(ER-) deficient mice are capable of responding to a
deciduogenic stimulus only in the presence of P4 (16 16A ).
Because of their vasoactive and mitogenic nature, PGs are implicated in
implantation and decidualization (reviewed in Ref. 17). PGs are
generated via cyclooxygenase (COX), which exists in two isoforms,
COX-1 and COX-2 (18). COX-2, but not COX-1, is essential for
implantation and decidualization (17). Among PGs, prostacyclin
(PGI2) and PGE2 are believed to be important
mediators of implantation (reviewed in Ref. 17). PGE2 binds
and activates a set of functionally distinct cell surface receptors,
EP1, EP2, EP3, and EP4,
which are classified on the basis of their pharmacological responses to
various agonists and antagonists of PGE2. They also exhibit
different characteristics with respect to their structures, tissue
distribution, and signal transduction mechanisms (19). While
PGI2 can bind to one G protein-coupled receptor known as IP
(19), PGI2 also functions as a ligand for peroxisome
proliferator-activated receptors (PPAR and PPAR
), members of a
nuclear hormone receptor superfamily (20, 21). Previous investigation
on periimplantation defects in Hoxa-10(-/-) mice
demonstrated poor vascular response and defective decidualization (8).
These results suggested that altered PG signaling could be one cause of
uterine failure in Hoxa-10(-/-) mice. Here we provide
evidence that uterine stromal responsiveness to P4 with
respect to both PG signaling and cell proliferation is defective in
Hoxa-10(-/-) mice.
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RESULTS |
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, a and b), but the exclusive
mesometrial stromal localization of EP3 was lost
with both mesometrial and lateral antimesometrial stromal expression at
low levels (Fig. 1, c–f). Myometrial expression of this gene was also
reduced in Hoxa-10(-/-) mice. With respect to
EP4, the stromal expression was considerably
down-regulated in Hoxa-10(-/-) uteri with little change in
epithelial expression (Fig. 1, g–j).
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, and PR that are
expressed in the stroma (16A, 28, 29). These genes were correctly
expressed in the uteri of Hoxa-10(-/-) mice on day 4 of
pregnancy (data not shown). Thus, the aberrant expression of
EP3 and EP4 in the
uterine stroma of Hoxa-10(-/-) mice appears to result
specifically from stromal Hoxa-10 deficiency.
EP3 and
EP4 Are Not Correctly Regulated by
P4 in Ovariectomized Hoxa-10(-/-)
Uteri
Since both EP3 and
EP4 are regulated by P4 in the mouse
uterus (26), we examined their regulation in Hoxa-10(-/-)
uteri under steroid hormonal stimulation. Levels of ovarian
P4 and estrogen and uterine responsiveness to these
steroids are important for preparing the uterus and embryo for
implantation (14). EP3 and
EP4 expression in the uterus is up-regulated by
P4 24 h after steroid injection of ovariectomized mice
(26), and the uterine distribution of these genes after P4
injection resembles that on day 4 of pregnancy. In
Hoxa-10(-/-) uteri, expression of
EP3 in the stroma and myometrium by
P4 was greatly reduced compared with that in wild-type mice
(Fig. 2, a–d). In contrast,
EP4 expression persisted at basal levels in
ovariectomized wild-type uteri in the absence of steroids. However,
P4 treatment up-regulated EP4
expression both in the stroma and epithelium in wild-type mice (Fig. 2, e and g). In Hoxa-10(-/-) uteri,
EP4 expression was generally lower but
especially in the stroma after P4 treatment (Fig. 2, f and
h). No differences were noted in EP2 expression
under similar conditions (data not shown). These results suggest that
Hoxa-10 mediates the effects of P4 in regulating the
correct expression of EP3 and
EP4 in the uterine stroma. Moreover, the
abnormal regulation of stromal EP3 and
EP4 in Hoxa-10(-/-) uteri is
apparently due neither to reduced levels of ovarian steroids nor
aberrant expression of their nuclear receptors, since exogenous
P4 injection in the ovariectomized
Hoxa-10(-/-) mice did not correct this aberration (Fig. 2), and PR and ER- are normally expressed in
these mice (data not shown).
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). Further, in
situ hybridization revealed similar localization and levels of
Hoxa-11 in P4-treated wild-type and
Hoxa-10(-/-) uteri (Fig. 3B). Lastly, the up-regulation of
c-myc by P4 and E2 at 6 h also
remained indistinguishable between wild-type and
Hoxa-10(-/-) mice (Fig. 3C). These results further confirm
that the aberrant regulation of EP3 and
EP4 in Hoxa-10(-/-) uteri is a
specific consequence of stromal deficiency of Hoxa-10 and that Hoxa-10
mediates the steroid hormonal regulation of these genes in the uterine
stroma.
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7-fold lower in
Hoxa-10(-/-) mice (Fig. 4
and Table 1). These data indicate that
Hoxa-10 is required for basal and for P4-induced stromal
cell proliferation.
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), resembling COX-2 induction at the
time of blastocyst attachment reaction (25). In
Hoxa-10(-/-) mice, epithelial COX-2 induction at 2 h
was normal, but stromal COX-2 induction at 24 h was considerably
reduced or absent in Hoxa-10(-/-) mice (Fig. 5, A and B).
A significant reduction of stromal COX-2 was also confirmed
by RNase protection assay (Fig. 5C). This provides evidence that loss
of COX-2 in the absence of Hoxa-10 is related to defective
decidualization in these mice. Alternatively, this could be a
consequence of decidualization failure in Hoxa-10(-/-)
mice.
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13 fold uterine weight
increases in response to intraluminal oil infusion, none of the five
Hoxa-10(-/-) mice showed any response. Further,
cPGI (n = 4), PGE2 (n = 5), or cPGI plus
PGE2 (n = 5) treatment did not improve the decidual
response in these mutants. The results are consistent with the idea
that the defective decidualization in Hoxa-10(-/-) mice
reflects altered downstream signaling of PGs due to aberrant expression
of their receptors. |
DISCUSSION |
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Appropriate levels of P4 and responsiveness of the uterus to this steroid are absolute requirements for decidualization (16 16A, 17). The failure of P4 to restore decidualization in Hoxa-10(-/-) mice (8) and the regulation of uterine Hoxa-10 by P4 (9) suggest that this gene is involved in mediating some important P4 actions in the uterus, and the identification of functional PR response elements (PREs) in the Hoxa-10 and Hoxa-11 intergenic region supports this notion (L. Ma and R. L. Maas, unpublished). Since Hoxa-10 is expressed in stromal cells in the periimplantation uterus and after steroid hormonal stimulation (6, 9), aberrant expression of EP3 and EP4 under these conditions in Hoxa-10(-/-) mice suggests that this homeobox protein acts as a direct or indirect mediator of P4 function in regulating these genes during implantation and decidualization. This is consistent with the observation that P4 induction of Hoxa-10 temporally precedes that of EP3/EP4. The correct expression of other P4-regulated uterine genes expressed in the epithelium (EP2 and Ar) or in the stroma (PR, Hoxa-11, and c-myc) in Hoxa-10(-/-) uteri further supports this hypothesis. The normal expression of ER and PR indicates that aberrant expression of EP3 and EP4 in the stroma is not the result of altered expression of these nuclear steroid receptors.
Reduced stromal cell proliferation in response to P4 and E2 in Hoxa-10(-/-) mice could potentially represent a consequence of altered PG signaling and may contribute to the defective decidual response in these mice. Alternatively, defective stromal cell proliferation in these mice could constitute a distinct phenomenon unrelated to PG signaling, since mammalian Hox genes are implicated in cell proliferation events (35). Cyclin D3, one of the G1 phase cyclins, is expressed in stromal cells at the onset of decidualization and is likely to activate cell cycle progression during this time (36). We have recently observed that expression of cyclin D3 fails to be up-regulated in Hoxa-10(-/-) uteri after application of a deciduogenic stimulus (36). This is also consistent with impaired stromal cell proliferation and points toward an underlying basis for the defective decidual response in Hoxa-10(-/-) mice.
Uterine COX-2 is induced by activated blastocysts at the
time of the attachment reaction and produces PGs that are essential for
implantation and decidualization (17, 25). Uterine and/or embryonic
COX-2 also appears to be important for implantation in
various species including sheep, mink, skunk, and baboon (37, 38, 39, 40).
COX-2 exhibits a unique biphasic cell-specific induction at
2 h and 24 h during the initial stages of decidualization
(Ref. 17 and Fig. 5
), and the stromal cell expression at 24 h
resembles the expression during blastocyst implantation (17, 25). The
loss of stromal COX-2 expression in
Hoxa-10(-/-) mice is intriguing, since these
COX-2 expressing cells exhibit the first decidual cell
reaction (17). Since uterine COX-2 is not directly regulated
by P4 and/or E2 (25), loss of stromal
COX-2 in these mice could be an indirect consequence of
defective decidualization. Alternatively, the loss of stromal
COX-2 in Hoxa-10(-/-) mice could indicate that
Hoxa-10 regulates COX-2 in this cell type. The second
speculation is supported by the observation that Hoxa-10 gene is
correctly expressed in the COX-2(-/-) uteri (17), implying
that Hoxa-10 is functionally upstream of COX-2 expression in
the subepithelial stroma.
The inability of exogenously administered PGs to improve decidual
responsiveness in Hoxa-10 mutants could be due to
inappropriate selection of time and doses, rapid metabolism, and/or
suboptimal delivery of these agents to the target cells. On the other
hand, the defective decidualization in Hoxa-10(-/-) mice
could result from altered PGE2 signal transduction due to
aberrant EP receptor expression. This phenotype of Hoxa-10deficiency is clearly distinct from that of
COX-2(-/-) mice (17). COX-2(-/-) mice, which
exhibit normal uterine cell proliferation and expression of
EP3 and EP4, respond to
exogenous cPGI and PGE2 with improved implantation and
decidualization (Ref. 17 and H. Lim, R. A. Gupta, B. C. Paria, D. E.
Moller, J. D. Morrow, R. N. DuBois, J. M. Trzaskos, and S. K. Dey, in
preparation). Therefore, aberrant expression of
EP3 and EP4 in
Hoxa-10(-/-) uteri suggests that signaling via these two
receptors is important for decidualization. Although
EP3-deficient female mice exhibit apparently
normal reproductive performance (41),
EP4-deficient mice exhibit neonatal lethality
and are therefore uninformative for this function (42). Thus,
EP4 could represent a potential candidate for
PGE2 signaling in decidualization. Although the
PGI2 cell surface receptor IP and nuclear
receptor PPAR are not detected in the mouse uterus at the
time of implantation, another PGI2 nuclear receptor
PPAR is expressed in stromal cells around the blastocyst
with the initiation of the attachment reaction and subsequent
decidualization. We have also found that COX-2 and
PPAR are coordinately expressed in stromal cells after
application of a deciduogenic stimulus (H. Lim, R. A. Gupta,
B. C. Paria, D. E. Moller, J. D. Morrow, R. N. DuBois, J. M. Trzaskos,
and S. K. Dey, in preparation). These observations suggest that
PGI2 signaling in implantation and decidualization is
mediated via PPAR, but not by IP or PPAR. We have preliminary
evidence that PPAR, like COX-2, fails to be
up-regulated in stromal cells after application of a deciduogenic
stimulus in Hoxa-10(-/-) mice (data not shown). Thus,
aberrant expression of EP3,
EP4, PPAR, and COX-2 in
Hoxa-10(-/-) uteri suggests that PG signaling plays an
important role in implantation and decidualization and that Hoxa-10 is
involved in regulating these signaling systems. Finally, implantation
and decidualization defects in Hoxa-10(-/-) mice are also
correlated with defective stromal cell proliferation in response to
steroid hormones. Based on our observation of reduced expression of
cyclin D3 with the onset of decidualization in
Hoxa-10(-/-) mice (36), this result is consistent with a
defect in progression through the G1 phase of the cell
cycle. Although PGs are involved in cell proliferation, whether
defective cell proliferation in Hoxa-10(-/-) mice results
from defective PG signaling will require further investigation.
The process of implantation involves regulated mitogenesis and vascular
permeability changes in the uterus, and ovarian steroids play pivotal
roles in these uterine events (14). P4 mediates a variety
of female reproductive functions as demonstrated in
PR-deficient mice (16). Our results show that
Hoxa-10(-/-) mice provide a good model to define the role
of P4 actions in the uterine stroma during implantation.
Interestingly, although a smaller percentage of
Hoxa-10(-/-) mice achieve successful pregnancy, about 40%
of Hoxa-10(-/-) mice succeed in initiating the
implantation reaction (8), suggesting that stromal defects in
Hoxa-10(-/-) mice do not completely negate the functions
of luminal epithelial cells for initial blastocyst contact. It is
possible that Hoxa-10 induces genes that are important for stromal cell
proliferation and differentiation in a P4-dominant
environment. Our results potentially identify the PG-signaling system
as acting functionally downstream of uterine Hoxa-10 in
implantation. Whether EP3,
EP4, PPAR, or COX-2 are
directly or indirectly regulated by Hoxa-10 requires further
investigation. Hoxa-10 is also implicated in the proliferation and
differentiation of the myeloid lineage during hematopoiesis (43, 44),
implying that this protein may also be capable of functioning similarly
in both contexts. Since Hox functions during embryogenesis have been
considered as regulators of local cell proliferation (35), the uterine
cell proliferative defect in Hoxa-10(-/-) mice could
provide a potentially powerful system with which to study the role of
Hox genes in cell proliferation and cell cycle control.
Collectively, our present findings suggest a novel role of Hoxa-10
in mediating certain actions of P4 in the uterine stroma
with respect to implantation and decidualization.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Hybridization Probes
For Northern hybridization and RNase protection assay,
32P-labeled antisense cRNA probes were generated, while for
in situ hybridization, sense and antisense
35S-labeled cRNA probes were generated using the
appropriate polymerases. Mouse-specific cDNAs to c-myc,
LIF, Ar, Hoxa-10, Hoxa-11,
COX-1, COX-2, PGE2 receptor subtypes
(EP2, EP3,
EP4), estrogen receptor- (ER-),
progesterone receptor (PR), tissue inhibitor of
metalloproteinase-2 (TIMP-2), matrix metalloproteinase-2
(MMP-2), rpL7, and rpL19 were used as
templates for generating probes for Northern blot hybridization,
in situ hybridization, or RNase protection assay (9, 17, 24, 25, 26, 27, 28, 29, 30).
In Situ Hybridization
In situ hybridization was performed as described
previously (23). Briefly, uteri were cut into 4–6 mm pieces and flash
frozen in Histo-Freeze (Fisher Scientific, Pittsburgh,
PA). Frozen sections (11 µm) were mounted onto
poly-L-lysine coated slides and fixed in cold 4%
paraformaldehyde in PBS. The sections were prehybridized and hybridized
at 45 C for 4 h in 50% formamide hybridization buffer containing
the 35S-labeled antisense cRNA probe (specific
activities 2 x 109 dpm/µg). 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). Sections hybridized with the corresponding
sense probe served as negative controls. Slides were poststained with
hematoxylin and eosin.
Northern Blot Hybridization
Total RNA was extracted from whole uteri pooled from 10–15 mice
at indicated times by a modified guanidine thiocyanate procedure (23, 45). Total RNA (6 µg) was denatured, separated by
formaldehyde-agarose gel electrophoresis, transferred to nylon
membranes, and cross-linked by UV irradiation (Spectrolinker, XL-1500,
Spectronics Corp., Westbury, NY). The blots were prehybridized,
hybridized with 32P-labeled antisense cRNA probe (specific
activities 2 x 109 dpm/µg), and washed as
described previously (23). After hybridization, the blots were washed
under stringent conditions, and the hybrids were detected by
autoradiography. The blots were stripped and rehybridized with
rpL7 probe as described previously (27).
RNase Protection Assay
32P-labeled cRNA probes were prepared as described
above. Analyses were performed as described previously (9, 46). For
each lane, 20 µg total RNA were hybridized for 16 h at 45 C
simultaneously with 3 x 105 cpm of RNA probes for
each of c-myc, PR, or COX-2 and with
2 x 104 cpm of rpL19 RNA probe and then
digested with 20 µg/ml RNase A and 1.5 µg/ml RNase T1. Protected
fragments were electrophoresed in 6% denaturing polyacrylamide gel and
analyzed by autoradiography. Band intensities were quantitated by
phosphorimager and normalized for loading differences with
rpL19.
Expression of Uterine Genes on Day 4 of Pregnancy in
Hoxa-10(-/-) Mice
Sections of day 4 (0900 h) pregnant uteri from wild-type or
Hoxa-10(-/-) mice were processed for in situ
hybridization for LIF, Ar, COX-1,
EP2, EP3,
EP4, TIM-2, MMP-2,
ER-, and PR mRNAs.
Uterine Responsiveness to E2 and
P4 in Hoxa-10(-/-) Mice
To determine whether Hoxa-10(-/-) mice respond
appropriately to P4, wild-type and
Hoxa-10(-/-) mice were ovariectomized and treated with
sesame oil (vehicle) or P4 (2 mg/mouse) with or without
E2 (100 ng/mouse) after 2 weeks of rest. Sesame oil and
steroid hormones were purchased from Sigma Chemical Co.
(St. Louis, MO). Uteri were collected 2, 6, or 24 h after the last
injection. Induction of PR (2, 6, and 24 h),
Hoxa-11 (6 h), c-myc (6 h)
EP3 (24 h), and EP4 (24
h) genes was assayed by RNase protection and/or in situ
hybridization.
To examine uterine cell-specific proliferation in response to E2 and/or P4, ovariectomized wild-type or Hoxa-10(-/-) mice were given an injection of E2 or P4 plus E2. After 22 h, they received an injection of [methyl-3H]thymidine (25 µCi/0.1 ml saline ip, specific activity, 40 mCi/mmol; RPI Corp., Mount Prospect, IL) and were killed 2 h later. Uteri were flash frozen and fixed in 4% paraformaldehyde after sectioning. Nuclear uptake of [3H]thymidine was detected in uterine sections by autoradiography (15) after 7–10 days of exposure. The autoradiographic signals (silver grains) were quantitated under a darkfield using the OPTIMA II program with an image analysis system (47).
Induction of COX-2 in the Hoxa-10(-/-) Uteri after
Application of a Deciduogenic Stimulus
To examine COX-2 induction in the Hoxa-10(-/-)
uteri in response to a deciduogenic stimulus, wild-type and
Hoxa-10(-/-) mice received intraluminal oil (25 µl) on
day 4 of pseudopregnancy. Uteri were collected at 2 or 24 h after
the oil infusion for Northern blot hybridization, in situ
hybridization, or RNase protection assay.
Decidual Response in Hoxa-10(-/-) Mice after
Supplementation of PGs
To induce decidualization, sesame oil (25 µl) was infused
intraluminally in one uterine horn on day 4 of pseudopregnancy; the
contralateral horn served as control. Mice were killed on day 8, and
uterine weights of the infused and noninfused (control) horns were
recorded to assess the extent of decidualization. PGE2
and/or cPGI (Cayman Chemical Co., Ann Arbor, MI) were prepared in 10%
EtOH-90% saline solution (20 µg/injection) and supplemented
intravenously at 1700 h on day 4 of pseudopregnancy followed by an
intraperitoneal injection on days 5–7.
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FOOTNOTES |
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This work was supported by NICHD/NIH grants as part of the National Cooperative Program on Markers of Uterine Receptivity for Blastocyst Implantation [(HD-29968) and HD-12304 to S.K.D.], and by NICHD Grant HD-35580 (to R.L.M.). H. L. was supported by a Kansas Health Foundation predoctoral fellowship, and L. M. is supported by an NIH National Research Service Award (1F32 HD-08264–01). Center grants in Reproductive Biology (HD-33994) and Mental Retardation (HD-02528) at the University of Kansas Medical Center provided access to various core facilities.
Received for publication January 6, 1999. Revision received February 23, 1999. Accepted for publication February 25, 1999.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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M. Q. Hassan, R. Tare, S. H. Lee, M. Mandeville, B. Weiner, M. Montecino, A. J. van Wijnen, J. L. Stein, G. S. Stein, and J. B. Lian HOXA10 Controls Osteoblastogenesis by Directly Activating Bone Regulatory and Phenotypic Genes Mol. Cell. Biol., May 1, 2007; 27(9): 3337 - 3352. [Abstract] [Full Text] [PDF]
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 R. Martin, M. B. Taylor, G. Krikun, C. Lockwood, G. E. Akbas, and H. S. Taylor Differential Cell-Specific Modulation of HOXA10 by Estrogen and Specificity Protein 1 Response Elements J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1920 - 1926. [Abstract] [Full Text] [PDF]
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 L. Huang, Y. Pu, D. Hepps, D. Danielpour, and G. S. Prins Posterior Hox Gene Expression and Differential Androgen Regulation in the Developing and Adult Rat Prostate Lobes Endocrinology, March 1, 2007; 148(3): 1235 - 1245. [Abstract] [Full Text] [PDF]
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A. Mukherjee, S. M. Soyal, R. Fernandez-Valdivia, M. Gehin, P. Chambon, F. J. DeMayo, J. P. Lydon, and B. W. O'Malley Steroid Receptor Coactivator 2 Is Critical for Progesterone-Dependent Uterine Function and Mammary Morphogenesis in the Mouse. Mol. Cell. Biol., September 1, 2006; 26(17): 6571 - 6583. [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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 G. S. Daftary and H. S. Taylor Endocrine Regulation of HOX Genes Endocr. Rev., June 1, 2006; 27(4): 331 - 355. [Abstract] [Full Text] [PDF]
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J. L. Sarno, F. Schatz, C. J. Lockwood, S.-T. J. Huang, and H. S. Taylor Thrombin and Interleukin-1{beta} Regulate HOXA10 Expression in Human Term Decidual Cells: Implications for Preterm Labor J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2366 - 2372. [Abstract] [Full Text] [PDF]
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H. N. Jabbour, R. W. Kelly, H. M. Fraser, and H. O. D. Critchley Endocrine Regulation of Menstruation Endocr. Rev., February 1, 2006; 27(1): 17 - 46. [Abstract] [Full Text] [PDF]
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 H. Yoshida, R. Broaddus, W. Cheng, S. Xie, and H. Naora Deregulation of the HOXA10 Homeobox Gene in Endometrial Carcinoma: Role in Epithelial-Mesenchymal Transition Cancer Res., January 15, 2006; 66(2): 889 - 897. [Abstract] [Full Text] [PDF]
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S. Tranguch, J. Cheung-Flynn, T. Daikoku, V. Prapapanich, M. B. Cox, H. Xie, H. Wang, S. K. Das, D. F. Smith, and S. K. Dey From The Cover: Cochaperone immunophilin FKBP52 is critical to uterine receptivity for embryo implantation PNAS, October 4, 2005; 102(40): 14326 - 14331. [Abstract] [Full Text] [PDF]
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 H. Du, G. S. Daftary, S. I. Lalwani, and H. S. Taylor Direct Regulation of HOXA10 by 1,25-(OH)2D3 in Human Myelomonocytic Cells and Human Endometrial Stromal Cells Mol. Endocrinol., September 1, 2005; 19(9): 2222 - 2233. [Abstract] [Full Text] [PDF]
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J.-W. Jeong, K. Y. Lee, I. Kwak, L. D. White, S. G. Hilsenbeck, J. P. Lydon, and F. J. DeMayo Identification of Murine Uterine Genes Regulated in a Ligand-Dependent Manner by the Progesterone Receptor Endocrinology, August 1, 2005; 146(8): 3490 - 3505. [Abstract] [Full Text] [PDF]
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X. Fei, H. Chung, and H. S. Taylor Methoxychlor Disrupts Uterine Hoxa10 Gene Expression Endocrinology, August 1, 2005; 146(8): 3445 - 3451. [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. Okada, G. Nie, and L. A. Salamonsen Requirement for Proprotein Convertase 5/6 during Decidualization of Human Endometrial Stromal Cells in Vitro J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 1028 - 1034. [Abstract] [Full Text] [PDF]
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K. Y Lee and F. J DeMayo Animal models of implantation Reproduction, December 1, 2004; 128(6): 679 - 695. [Abstract] [Full Text] [PDF]
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K. Tamura, T. Hara, M. Kutsukake, K. Iwatsuki, M. Yanagida, M. Yoshie, and H. Kogo Expression and the Biological Activities of Insulin-Like Growth Factor-Binding Protein Related Protein 1 in Rat Uterus during the Periimplantation Period Endocrinology, November 1, 2004; 145(11): 5243 - 5251. [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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R. Grummer, S.W. Hewitt, O. Traub, K.S. Korach, and E. Winterhager Different Regulatory Pathways of Endometrial Connexin Expression: Preimplantation Hormonal-Mediated Pathway Versus Embryo Implantation-Initiated Pathway Biol Reprod, July 1, 2004; 71(1): 273 - 281. [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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 L. Huang, Y. Pu, S. Alam, L. Birch, and G. S. Prins Estrogenic Regulation of Signaling Pathways and Homeobox Genes During Rat Prostate Development J Androl, May 1, 2004; 25(3): 330 - 337. [Full Text] [PDF]
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T. Daikoku, H. Song, Y. Guo, A. Riesewijk, S. Mosselman, S. K. Das, and S. K. Dey Uterine Msx-1 and Wnt4 Signaling Becomes Aberrant in Mice with the Loss of Leukemia Inhibitory Factor or Hoxa-10: Evidence for a Novel Cytokine-Homeobox-Wnt Signaling in Implantation Mol. Endocrinol., May 1, 2004; 18(5): 1238 - 1250. [Abstract] [Full Text] [PDF]
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M. Mericskay, J. Kitajewski, and D. Sassoon Wnt5a is required for proper epithelial-mesenchymal interactions in the uterus Development, May 1, 2004; 131(9): 2061 - 2072. [Abstract] [Full Text] [PDF]
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V. Rider, E. Thomson, and C. Seifert Transit of Rat Uterine Stromal Cells through G1 Phase of the Cell Cycle Requires Temporal and Cell-Specific Hormone-Dependent Changes on Cell Cycle Regulators Endocrinology, December 1, 2003; 144(12): 5450 - 5458. [Abstract] [Full Text] [PDF]
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Y.-P. Cheon, X. Xu, M. K. Bagchi, and I. C. Bagchi Immune-Responsive Gene 1 Is a Novel Target of Progesterone Receptor and Plays a Critical Role during Implantation in the Mouse Endocrinology, December 1, 2003; 144(12): 5623 - 5630. [Abstract] [Full Text] [PDF]
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B. Chen, D. Zhang, and J. W. Pollard Progesterone Regulation of the Mammalian Ortholog of Methylcitrate Dehydratase (Immune Response Gene 1) in the Uterine Epithelium during Implantation through the Protein Kinase C Pathway Mol. Endocrinol., November 1, 2003; 17(11): 2340 - 2354. [Abstract] [Full Text] [PDF]
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M. W. M. Yao, H. Lim, D. J. Schust, S. E. Choe, A. Farago, Y. Ding, S. Michaud, G. M. Church, and R. L. Maas Gene Expression Profiling Reveals Progesterone-Mediated Cell Cycle and Immunoregulatory Roles of Hoxa-10 in the Preimplantation Uterus Mol. Endocrinol., April 1, 2003; 17(4): 610 - 627. [Abstract] [Full Text] [PDF]
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H. Song, H. Lim, B. C. Paria, H. Matsumoto, L. L. Swift, J. Morrow, J. V. Bonventre, and S. K. Dey Cytosolic phospholipase A2{alpha} is crucial for 'on-time' embryo implantation that directs subsequent development Development, March 8, 2003; 129(12): 2879 - 2889. [Abstract] [Full Text] [PDF]
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W.-g. Ma, H. Song, S. K. Das, B. C. Paria, and S. K. Dey Estrogen is a critical determinant that specifies the duration of the window of uterine receptivity for implantation PNAS, March 4, 2003; 100(5): 2963 - 2968. [Abstract] [Full Text] [PDF]
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G.-Y. Nie, Y. Li, H. Minoura, J. K. Findlay, and L. A. Salamonsen Specific and Transient Up-Regulation of Proprotein Convertase 6 at the Site of Embryo Implantation and Identification of a Unique Transcript in Mouse Uterus During Early Pregnancy Biol Reprod, February 1, 2003; 68(2): 439 - 447. [Abstract] [Full Text] [PDF]
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J. J. Kim, H. S. Taylor, G. E. Akbas, I. Foucher, A. Trembleau, R. C. Jaffe, A. T. Fazleabas, and T. G. Unterman Regulation of Insulin-Like Growth Factor Binding Protein-1 Promoter Activity by FKHR and HOXA10 in Primate Endometrial Cells Biol Reprod, January 1, 2003; 68(1): 24 - 30. [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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S. Curtis Hewitt, E. H. Goulding, E.M. Eddy, and K. S. Korach Studies Using the Estrogen Receptor {alpha} Knockout Uterus Demonstrate That Implantation but Not Decidualization-Associated Signaling Is Estrogen Dependent Biol Reprod, October 1, 2002; 67(4): 1268 - 1277. [Abstract] [Full Text] [PDF]
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G. S. Prins, W. Y. Chang, Y. Wang, and R. B. van Breemen Retinoic Acid Receptors and Retinoids Are Up-Regulated in the Developing and Adult Rat Prostate by Neonatal Estrogen Exposure Endocrinology, September 1, 2002; 143(9): 3628 - 3640. [Abstract] [Full Text] [PDF]
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K. D. Papay and T. G. Kennedy Characterization of Temporal and Cell-Specific Changes in Transcripts for Prostaglandin E2 Receptors in Pseudopregnant Rat Endometrium Biol Reprod, June 1, 2000; 62(6): 1515 - 1525. [Abstract] [Full Text]
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J. Reese, N. Binart, N. Brown, W.-g. Ma, B. C. Paria, S. K. Das, P. A. Kelly, and S. K. Dey Implantation and Decidualization Defects in Prolactin Receptor (PRLR)-Deficient Mice Are Mediated by Ovarian But Not Uterine PRLR Endocrinology, May 1, 2000; 141(5): 1872 - 1881. [Abstract] [Full Text] [PDF]
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J. Tan, B. C. Paria, S. K. Dey, and S. K. Das Differential Uterine Expression of Estrogen and Progesterone Receptors Correlates with Uterine Preparation for Implantation and Decidualization in the Mouse Endocrinology, November 1, 1999; 140(11): 5310 - 5321. [Abstract] [Full Text]
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S. K. Das, J. Tan, S. Raja, J. Halder, B. C. Paria, and S. K. Dey Estrogen Targets Genes Involved in Protein Processing, Calcium Homeostasis, and Wnt Signaling in the Mouse Uterus Independent of Estrogen Receptor-alpha and -beta J. Biol. Chem., September 8, 2000; 275(37): 28834 - 28842. [Abstract] [Full Text] [PDF]
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