| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Departments of Veterinary Biosciences (Y.-P.C., I.C.B.) and Molecular and Integrative Physiology (M.K.B.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61802; and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030
Address all correspondence and requests for reprints to: Indrani C. Bagchi, Department of Veterinary Biosciences, University of Illinois at Urbana-Champaign, Urbana, Illinois 61802. E-mail: ibagchi{at}uiuc.edu.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The majority of cellular actions of P are mediated through intracellular P receptors (PRs), PR-A and PR-B, which are well-studied gene regulators (10). It is postulated that hormone-occupied PRs trigger the expression of specific gene networks in the uterine cells, and the products of these genes mediate the hormonal effects during implantation. Although P has a profound influence on implantation, previous studies in rodents have identified only a few genes that are under P regulation in the uterus. These include the genes encoding amphiregulin (growth factor), Hoxa-10, and Hoxa-11 (homeobox proteins), Indian hedgehog (morphogen), calcitonin, and proenkephalin (peptide hormones), and histidine decarboxylase (enzyme involved in regulation of inflammatory response) (5, 11, 12, 13, 14, 15, 16, 17, 18). These previously identified genes, however, cannot account for the full range of physiological and biochemical events influenced by P in the preimplantation uterus. To understand how P regulates implantation, it is essential to identify a broader spectrum of genes that are regulated by PR at the time of implantation.
To achieve this goal, we used RU486, a well-characterized antagonist of PR function during pregnancy. RU486 counteracts PR-dependent pathways by binding to the receptor and impairing its gene regulatory function (19, 20). We used oligonucleotide microarrays to identify the genes whose uterine expression is markedly altered at the time of implantation by RU486-complexed PR (21). Mice on d 3 of pregnancy were treated with either vehicle (sesame oil) or RU486 (8 mg/kg body weight) and euthanized 24 h later on d 4, the day of implantation. The RNA samples obtained from uteri of animals treated with or without RU486 were hybridized to oligonucleotide probe arrays (GeneChip; Affymetrix, Santa Clara, CA) corresponding to 12,000 genes. Using this methodology, we identified several known genes that were down regulated in the uterus in response to RU486 (21). Interestingly, we found that the expression of Irg1 mRNA in the preimplantation uterus was suppressed significantly (
8-fold) by RU486 treatment. A previous study reported that Irg1 mRNA expression is induced in the RAW 264.7 macrophage cell line upon lipopolysaccharides stimulation (22). In this study, we analyzed the spatio-temporal expression of Irg1 in the pregnant uterus and investigated its functional role in the implantation process.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Animals and tissue collection
All experiments involving animals were approved by the Animal Care Committee at the University of Illinois at Urbana-Champaign, and the studies were conducted in accordance with the National Institutes of Health standards for the use and care of animals. Female mice (CD-1 from Charles River, Wilmington, MA), in proestrus, were mated with adult males. The presence of a vaginal plug after mating was designated as d 1 of pregnancy. The animals were killed at various stages of gestation and the uteri collected. The uteri were freed of embryos by repeated flushing. In some experiments, animals were ovariectomized and, 14 d later, were injected sc with E (2 µg/kg body weight), P (40 mg/kg body weight), or vehicle (cottonseed oil), as described in Results. The mice were killed 24 h after final injection.
The PR knockout mice (PRKO) mice were bred, and homozygotes were confirmed by genotyping as described previously (21).
Northern blot analysis
For Northern blot analysis, 20–30 µg of total RNA was separated by formaldehyde agarose gel electrophoresis and transferred to Positively Charged Nylon Membrane (Ambion, Austin, TX). After transfer, the membranes were cross-linked with UV Crosslinker (Stratagene, La Jolla, CA). Blots were hybridized in ULTRAhyb buffer according to the manufacturer’s specifications (Ambion). Hybridization was carried out overnight in the buffer containing 106 cpm/ml of a 32P-labeled Irg1 cDNA fragment (900–1170 bp of mouse Irg1 gene). After washing, the membrane was exposed to x-ray films for 16–48 h. The intensities of signals on the autoradiogram were estimated by densitometric scanning. To correct for RNA loading, the obtained signals were normalized with respect to the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) signal in the same blot. For this the filters were stripped of the radioactive probe by washing for 10 min in 0.5% sodium dodecyl sulfate at 95 C. The blots were then reprobed with a 32P-labled GAPDH probe (361–750 bp of mouse GAPDH cDNA) as described above. Densitometric analysis of the bands in the Northern blots was performed using a PhosphorImager system (Molecular Dynamics, Inc., Sunnyvale, CA). Blots were exposed to a PhosphorImager screen and the PhosphorImager’s ImageQuant software (Molecular Dynamics) was used for quantitative analysis of Irg1 expression corrected to expression of GAPDH.
In situ hybridization
Uterine tissues from pregnant animals were collected and frozen. Tissues were fixed in 4% paraformaldehyde at 4 C. Cryostat sections were cut at 8 µm and attached to 3-aminopropyl triethyl silane (Sigma)-coated slides. In situ hybridization was performed with digoxigenin (DIG)-labeled sense or antisense RNA probes complimentary to nucleotides 900-1170 bp of mouse Irg1 gene. DIG-labeled RNA probes were synthesized from Irg1 cDNA using T3 or T7 RNA polymerase and DIG-labeled nucleotides according to manufacturer’s specifications (Roche Diagnostics Corp., Indianapolis, IN). Prehybridization was carried out in a damp chamber at 55 C for 60 min in hybridization buffer [50% formamide, 5 x standard saline solution (SSC), 2% blocking reagent, 0.02% sodium dodecyl sulfate, 0.1% N-laurylsarcosine). Hybridization was carried out at 55 C overnight in a damp humidified chamber. To develop the substrate, sections were sequentially washed in 2 x SSC, 1 x SSC, and 0.1 x SSC for 15 min in each buffer at 37 C. Sections were then incubated with anti-DIG alkaline phosphatase-conjugated antibody. Excess antibody was washed away, and the color substrate (nitroblue tetrazolium salt and 5-bromo-4-chloro-3-indoylphosphate) was added. Slides were allowed to develop in the dark, and the color was visualized under light microscopy until maximum levels of staining were achieved. The reaction was stopped, and the slides were counterstained in nuclear fast red for 5 min. The slides were washed in water, dehydrated, and cover-slipped. Control incubations used a DIG-labeled RNA sense strand and were performed under identical conditions.
Synthesis and sequence of oligodeoxynucleotides (ODNs)
The ODNs containing phosphorothioate linkages in all positions were synthesized based on the sequence of the mouse Irg1 gene (GenBank no. L38281) and purified with polyacrylamide gel electrophoresis. The sequences of the first set of Irg1 ODNs (19 nucleotides in length) were: sense ODN-1, 5'-AGGGTTCGGTGCCTTCTAT-3', and antisense ODN-1, 5'-ATAGAAGGCACCGAACCCT-3'. The sequences of the second set of Irg1 ODNs (18 nucleotides in length) were: sense ODN-2, 5'-TACGTAAACAGGCCCTTC-3', and antisense ODN-2, 5'-T-GAAGGGCCTGTTTACGTA-3'. The antisense ODN-1 and ODN-2 were complementary to bases 993-1011 and 1228–1245, respectively. The ODNs corresponding to tissue plasminogen activator (t-PA; GenBank accession no. J03520) were sense ODN, 5'-GCAAAATGAAGAGAGAGCTG-3', and antisense ODN, 5'-CAGCTCTCTCTTCATTTTGC-3'.
Treatment of animals with ODNs
Treatment of animals with ODNs was performed as described previously with minor modifications (23). Briefly, mice were deeply anesthetized, and an incision was made in the lower abdomen. The ODNs were mixed with N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methylsulfate (Roche Diagnostics Corp.) and 20% F127 Pluronic gel (Sigma). The solution was maintained in liquid form at 4 C before injection. Fifty microliters of this ODN solution were taken in prechilled syringes and injected into each uterine horn. The incision was then closed, and the animals were returned to their cages.
Statistical analysis
Statistical evaluation of the data representing the effects of ODN treatments on the number of corpora lutea (CL) and implanted embryos (IE) in the uterus was performed using the Student’s t test. All data were calculated as mean ± SD. P < 0.05 were considered statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, using the antisense Irg1 probe, we observed a strong hybridization signal in the luminal epithelial cells of the uterine sections obtained from P-treated ovariectomized mice (Fig. 1C). In contrast, no signal was detected in the luminal epithelial cells of the uteri of either vehicle- or E-treated animals (Fig. 1, A and B). Control uterine sections (P-treated ovariectomized mice) hybridized with the corresponding sense RNA probe of equal length did not exhibit any significant signal (Fig. 1D). We did not detect any Irg1 mRNA signal in the glandular epithelium, stroma, or myometrium. These results demonstrated that the luminal epithelial cells are the actual sites of synthesis of Irg1 mRNA and that Irg1 expression in rodent uteri is indeed under P regulation consistent with its down-regulation by RU486 in the microarray analysis.
|
). No signal corresponding to Irg1 mRNA was observed in the uterine sections of vehicle-treated ovariectomized wild-type mice (Fig. 2A). As expected, a significant induction of Irg1 mRNA was observed in the surface epithelial cells of the wild-type uteri upon administration of P (Fig. 2B). In contrast, Irg1 mRNA could not be detected in the uteri of ovariectomized PRKO mice upon either vehicle or P treatment (Fig. 2, C and D, respectively). These results clearly indicated that PR is essential for Irg1 gene expression in the uterus.
|
(top panel), the Irg1 transcript was undetectable on d 1–2 of pregnancy. A faint band of about 2.2 kb corresponding to the Irg1 mRNA appeared on d 3. A marked elevation in the level of Irg1 transcript was observed on d 4, the day of implantation. The signal corresponding to Irg1 declined sharply thereafter and was undetectable on d 5–6 of pregnancy. The relative level of expression of Irg1 was estimated by densitometric scanning, followed by normalization with respect to the control GAPDH mRNA signal. The level of Irg1 mRNA on d 4 was about 20-fold higher than the level on d 2 of gestation (Fig. 3B). These results indicate that a transient surge of Irg1 mRNA expression occurs in the uterus on d 4 of gestation, presumably in response to P, and this induction precisely coincides with the time of implantation.
|
). Consistent with the Northern blot analysis, uterine sections obtained from d 2, 3, and 6 pregnant animals exhibited relatively weak or no hybridization signal (panels D2, D3, and D6, respectively). In contrast, specific hybridization signal was observed in the epithelial cells of the uterine sections obtained from d 4 pregnant animals (panel D4). Control uterine sections (pregnant, d 4) hybridized with the corresponding sense RNA probe of equal length did not exhibit any significant signal (panel D4/S), indicating the specificity of the reaction. These results further confirm that Irg1 mRNA is transiently expressed in the luminal epithelial cells of pregnant uterus overlapping the window of implantation. Moreover, this spatial pattern of Irg1 expression is similar to the one observed in the uteri of ovariectomized mice in response to P treatment (Fig. 1
).
|
To block the transient uterine expression of Irg1 mRNA on d 4 of pregnancy, we used two different phosphorothioate antisense ODNs, antisense ODN-1 and antisense ODN-2, of different base compositions directed against the Irg1 mRNA. We also used the complementary sense ODNs, sense ODN-1 and sense ODN-2 as control ODNs. Both uterine horns of mice on d 2 of pregnancy were injected with increasing doses (1, 3, 5, and 10 µg) of either Irg1 antisense ODNs or the corresponding sense ODNs. Forty-eight hours after this procedure, the animals were killed, uteri were collected, and mRNAs were isolated for Northern blot analysis. In the experiment described in Fig. 5 (upper panel), the uterine horns that were treated with 3 µg of antisense ODN-1 (lane 2) exhibited markedly reduced Irg1 mRNAs compared with the horns that were injected with the same amount of sense ODN-1 (lane 1). Similar results were obtained with Irg1 antisense ODN-2 and sense ODN-2 (data not shown). Hybridization of the blot with GAPDH displayed signals of comparable intensities in both the lanes (Fig. 5, lower panel), indicating that GAPDH expression was not significantly affected by either sense or antisense Irg1 ODNs. We found that a dose of 3–5 µg ODN is optimal for suppression of Irg1 mRNAs in the pregnant uterus. Although a lower dose (1 µg) of ODN did not inhibit Irg1 mRNA expression sufficiently, a dose of 10 µg or higher resulted in nonspecific inhibition (data not shown). These results demonstrate that antisense ODN intervention on d 2 of pregnancy results in suppression of Irg1 mRNA expression in the mouse uterus on the day of implantation (d 4).
|
To examine this prediction, we injected uterine horns of pregnant mice (d 2) with sense and antisense ODNs directed against t-PA mRNA. As shown in Fig. 6A, the level of t-PA mRNA was markedly suppressed by antisense but not sense ODN treatment. We then examined the effects of these treatments on the implantation process. Mice on d 2 of pregnancy were treated with vehicle (control) or t-PA ODNs. Whereas one uterine horn was injected with antisense t-PA ODNs, the other horn received the corresponding sense ODNs. After surgery, the animals were returned to their cages and killed on d 9 of gestation. When the uteri were collected on d 9 of gestation, we did not observe any significant difference in the number of IEs in sense or antisense ODN-treated animals (Fig. 6B). Statistical analyses indicated that the number of IEs in sense or antisense t-PA ODN-treated mice remained essentially the same (Fig. 6C). These results showed that the ODN intervention did not produce any global inhibitory effect on implantation.
|
). In the test animals (n = 7), the uterine horns injected with the sense ODN-1 showed no significant change in the number of IEs compared with the control animals (Fig. 7, B and C, left horn). We also noted that the number of CL in the ovaries is similar to the number of IEs in control (CL, 7.2 ± 0.8; IE, 6.8 ± 1.0) or sense ODN-treated uterine horn (CL, 7.3 ± 1.3; IE, 6.7 ± 1.2) (Fig. 7D). These results ensured that the surgical interventions during early pregnancy had no adverse effect on the transport of embryo from oviduct to uterus. Interestingly, we observed that the uterine horns treated with antisense ODN-1 exhibited a dramatic decrease in the number of IEs (Fig. 7, B and C, right horn). In the antisense ODN-treated uteri (CL, 7.2 ± 0.9; IE, 1.3 ± 1.2), the magnitude of reduction in the number of IEs ranged from 50–100%. For example, in certain experiments, there was no visible embryo in the antisense ODN-treated horn (Fig. 7C). In other experiments, however, one third of IEs were observed upon antisense ODN treatment (Fig. 7B). The Student’s t test was used to compare the data for the number of IEs, and a significant difference with respect to implantation sites was obtained after treatment with either antisense or sense ODNs (Fig. 7D). Another group of pregnant animals (n = 7) were injected with Irg1 sense or antisense ODN-2. These studies also showed 50–90% reduction in the number of IEs after administration of antisense ODN. Taken together, these results demonstrate that antisense Irg1 ODNs, when injected into the uterine horns on d 2 of gestation, can severely impair implantation of embryos, and this phenotype is likely representative of the loss of Irg1 mRNA.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Lee et al. (22) first cloned Irg1 as a novel lipopolysaccharide-inducible gene that mapped to the distal portion of mouse chromosome 14. They reported that Irg1 is induced in macrophage cells in vitro upon exposure to the lipopolysaccharides. The human homolog of Irg1 was subsequently identified and displayed 83% identity to the mouse gene at the nucleotide level. The Irg1 cDNAs were isolated from bone and spleen cDNA libraries, indicating that this gene is expressed in these tissues. The expression pattern and regulation of Irg1 in these or any other tissue, however, remained uncharacterized. Our present study shows that, in the uteri of pregnant mice, Irg1 is expressed in the luminal epithelial cells in an implantation stage-specific manner (Fig. 4). The expression of the Irg1 gene increased by d 3 of gestation and reached a peak on d 4, the day of implantation. On d 5, the expression of the gene declined abruptly and fell below detection limits (Fig. 3). It is of interest to note that the spatio-temporal expression of Irg1 closely follows that of PR in the uterine luminal epithelium during early pregnancy. In mice, the level of PR in the luminal epithelial cells is maximal on d 3 and 4 of pregnancy and then decreases sharply on d 5 (21). Although PR disappears from the luminal epithelium after implantation, a high level of this receptor continues to express in the stromal cells during decidualization (21). It is conceivable that the loss of PR in the luminal epithelial cells in the postimplantation period is directly linked to the down-regulation of Irg1 expression in the same cellular compartment of the uterus. Indeed, our studies using PRKO mice showed that PR is essential for the expression of Irg1 in the luminal epithelial cells of the uterus (Fig. 3). Our studies, however, did not address whether PR regulates Irg1 expression by interacting directly with its promoter or acts indirectly by inducing the synthesis of a regulatory factor, which in turn modulates Irg1 promoter activity.
One way of investigating the biological role of Irg1 during implantation is by creating an Irg1-deficient mutant mouse model and analyzing its phenotype. We have, however, taken an alternative approach, which is less time consuming, to investigate Irg1 function by blocking its expression in the uterine tissue by using antisense ODNs targeted against its mRNA. We had previously developed a methodology to knock down the expression of specific uterine genes in the preimplantation rat uterus by injecting antisense ODNs targeted to the mRNA transcripts in preimplantation rat uteri (29). Antisense ODNs have also been used to regulate target gene expression in mouse uterus (30, 31). In this study, we demonstrated that administration of antisense ODNs, targeted specifically against Irg1 mRNAs, into the lumen of the preimplantation phase uterus results in a marked reduction (80%) in the number of IEs. Similar treatment with the corresponding sense ODNs exhibited no effect on implantation. The antisense ODN intervention also markedly suppressed the steady-state level of the Irg1 mRNA in the uterus, without affecting the expression of unrelated genes. These results collectively suggest that the block in embryonic implantation upon administration of the antisense ODNs into the uterus is likely to be a direct phenotypic consequence of the suppression of Irg1 gene expression in the implantation phase of gestation.
An important aspect of this work is the successful application of the antisense ODN strategy to block gene expression in mouse uterus. In the process of developing this technology, we have addressed a number of concerns that were raised previously regarding nonspecific inhibition of gene expression caused by ODN treatment. We have shown that 1) treatment of pregnant uteri with two different Irg1 antisense ODNs, antisense ODN-1 and antisense ODN-2, possessing different base compositions produced the same phenotype, but the corresponding sense ODNs of equal length had no effect; and 2) the antisense, but not the sense, ODNs inhibited target mRNA expression, whereas neither inhibited nontarget mRNAs when optimal amounts were used. We also examined whether nonspecific phenotypic effects are caused by ODN-mediated suppression of gene expression. Inhibition of expression of t-PA, an unrelated gene, by antisense ODNs did not lead to a block in implantation. Finally, our studies also addressed the concern that sense or antisense ODNs may exert a general toxic effect on the transport of the fertilized embryo into the uterus and its subsequent development. In our studies, we have observed that administration of optimal amounts of two different sense or antisense t-PA ODNs (3 µg) on d 2 of pregnancy did not have any significant effect on implantation or subsequent embryo development until d 9 of gestation. The number of implantation sites in the uterus was in nice agreement with the number of CL generated in the ovary. Therefore, it is highly unlikely that the administration of optimal levels of ODNs or the vehicle exerts any general deleterious effect on the embryo. The antisense ODN methodology, therefore, emerges as a powerful tool to manipulate the expression of a gene in utero and to analyze its function.
Although Irg1 is essential for implantation, its mechanism of action in the pregnant uterus remains unclear. Analysis of its putative protein sequence revealed a consensus sequence for the glycosaminoglycan (GAG) attachment site, a signature motif for proteoglycan binding (22). Proteoglycans are proteins bearing one or more GAG polysaccharides. They have been credited, in one system or another, in controlling numerous cellular processes, including cell adhesion, spreading, migration, matrix assembly, and extracellular proteolysis (32, 33). Previous studies have shown that heparin sulfate proteoglycans participate in adhesive interactions occurring between human trophoblastic and uterine epithelial cell lines (34). Studies in mice also revealed that heparin sulfate synthesis increased 4- to 5-fold at the periimplantation stage and was required for embryo attachment and outgrowth in vitro (35, 36). One can speculate that after P induction, Irg1 protein interacts with the proteoglycans to modulate adhesive function in embryo-uterine interaction during implantation.
The GAG attachment motif also exists in many growth factors and cytokines, such as fibroblast growth factor, IL-7, TGF-ß, granulocyte-macrophage colony-stimulating factor, and macrophage colony-stimulating factor (33). These factors are sequestered and presented to target cell by extracellular or cell surface proteoglycans (33). For example, proteoglycans serves as a reservoir of matrix-bound fibroblast growth factor. The active growth factor is released upon proteolysis of the proteoglycan core protein or partial degradation of the GAG polysaccharide chains during tissue growth and remodeling. The released factor then acts in an autocrine or paracrine manner by binding to its cell surface receptor, and it has been suggested that it serves as an adhesion trigger (33, 37). Whether Irg1, which is maximally expressed on d 4 coincident with the adhesive phase of the uterus, performs a similar function during implantation remains to be examined. Future studies will investigate the molecular pathways by which Irg1 protein acts in the preimplantation uterus to exert its critical effects.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Abbreviations: CL, Corpora lutea; DIG, digoxigenin; E, estrogen; GAG, glycosaminoglycan; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; IE, implanted embryo; Irg1, immune-responsive gene 1; ODN, oligodeoxynucleotide; P, progesterone; PR, progesterone receptor; PRKO, progesterone receptor knockout mice; SSC, standard saline solution; t-PA, tissue plasminogen activator.
Received May 13, 2003.
Accepted for publication August 21, 2003.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  T. E Spencer, O. Sandra, and E. Wolf Genes involved in conceptus-endometrial interactions in ruminants: insights from reductionism and thoughts on holistic approaches Reproduction, February 1, 2008; 135(2): 165 - 179. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. G Lea and O. Sandra Immunoendocrine aspects of endometrial function and implantation Reproduction, September 1, 2007; 134(3): 389 - 404. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Pan, L. Zhu, Y. Deng, and J. W. Pollard Microarray Analysis of Uterine Epithelial Gene Expression during the Implantation Window in the Mouse Endocrinology, October 1, 2006; 147(10): 4904 - 4916. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E.A. Campbell, L. O'Hara, R.D. Catalano, A.M. Sharkey, T.C. Freeman, and M. H. Johnson Temporal expression profiling of the uterine luminal epithelium of the pseudo-pregnant mouse suggests receptivity to the fertilized egg is associated with complex transcriptional changes Hum. Reprod., October 1, 2006; 21(10): 2495 - 2513. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Li, Z. Gang, H. Yuling, X. Luokun, X. Jie, L. Hao, W. Li, H. Chunsong, L. Junyan, J. Mingshen, et al. Different Neurotropic Pathogens Elicit Neurotoxic CCR9- or Neurosupportive CXCR3-Expressing Microglia J. Immunol., September 15, 2006; 177(6): 3644 - 3656. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Niklaus and J. W. Pollard Mining the Mouse Transcriptome of Receptive Endometrium Reveals Distinct Molecular Signatures for the Luminal and Glandular Epithelium Endocrinology, July 1, 2006; 147(7): 3375 - 3390. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 S. Y. Han, N. K. Lee, K. H. Kim, I. W. Jang, M. Yim, J. H. Kim, W. J. Lee, and S. Y. Lee Transcriptional induction of cyclooxygenase-2 in osteoclast precursors is involved in RANKL-induced osteoclastogenesis Blood, August 15, 2005; 106(4): 1240 - 1245. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J Kimber Leukaemia inhibitory factor in implantation and uterine biology Reproduction, August 1, 2005; 130(2): 131 - 145. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 R. D. Catalano, M. H. Johnson, E. A. Campbell, D. S. Charnock-Jones, S. K. Smith, and A. M. Sharkey Inhibition of Stat3 activation in the endometrium prevents implantation: A nonsteroidal approach to contraception PNAS, June 14, 2005; 102(24): 8585 - 8590. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
