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ABSTRACT: In order to understand the biology of the endometrium and potentially develop new diagnostic tools and treatments for endometrial diseases, the highly orchestrated gene expression/regulation that occurs within the uterus must first be understood. Even though a wealth of information on endometrial gene expression/regulation is available, this information is scattered across several different resources in formats that can be difficult for the average bench scientist to query, integrate, and utilize. The Endometrium Database Resource (EDR) was created as a single evolving resource for protein- and micro-RNA-encoding genes that have been shown by gene expression microarray, Northern blot, or other experiments in the literature to have their expression regulated in the uterus of humans, mice, rats, cows, domestic pigs, guinea pigs, and sheep. Genes are annotated in EDR with basic gene information (eg, gene symbol and chromosome), gene orthologs, and gene ontologies. Links are also provided to external resources for publication/s, nucleic and amino acid sequence, gene product function, and Gene Expression Omnibus (GEO) phase expression graph information. The resource also allows for direct comparison of relative gene expression in different microarray experiments for genes shown in the literature to be differentially expressed in the uterus. It is available via a user-friendly, web-based interface and is available without charge or restriction to the entire scientific community. The EDR can be accessed at http://edr.research.bcm.edu.
Molecular Endocrinology 01/2013; · 4.54 Impact Factor
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Heather L Franco,
Daisy Dai, Kevin Y Lee,
Cory A Rubel,
Dennis Roop,
Derek Boerboom,
Jae-Wook Jeong,
John P Lydon,
Indrani C Bagchi,
Milan K Bagchi,
Francesco J DeMayo
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ABSTRACT: WNT4, a member of the Wnt family of ligands, is critical for the development of the female reproductive tract. Analysis of Wnt4 expression in the adult uterus during pregnancy indicates that it may play a role in the regulation of endometrial stromal cell proliferation, survival, and differentiation, which is required to support the developing embryo. To investigate the role of Wnt4 in adult uterine physiology, conditional ablation of Wnt4 using the PR(cre) mouse model was accomplished. Ablation of Wnt4 rendered female mice subfertile due to a defect in embryo implantation and subsequent defects in endometrial stromal cell survival, differentiation, and responsiveness to progesterone signaling. In addition to altered stromal cell function, the uteri of PR(cre/+)Wnt4(f/f) (Wnt4(d/d)) mice displayed altered epithelial differentiation characterized by a reduction in the number of uterine glands and the emergence of a p63-positive basal cell layer beneath the columnar luminal epithelial cells. The altered epithelial cell phenotype was further escalated by chronic estrogen treatment, which caused squamous cell metaplasia of the uterine epithelium in the Wnt4(d/d) mice. Thus, WNT4 is a critical regulator not only of proper postnatal uterine development, but also embryo implantation and decidualization.
The FASEB Journal 12/2010; 25(4):1176-87. · 5.71 Impact Factor
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ABSTRACT: During embryonic development, Foxa2 is required for the formation of the node and notochord, and ablation of this gene results in defects in gastrulation, neural tube patterning, and gut morphogenesis. Foxa2 has been shown to be expressed specifically in the glandular epithelium of the murine uterus. To study the uterine function of Foxa2, this gene was conditionally ablated in the mouse uterus by crossing mice with floxed Foxa2 alleles, Foxa2(loxP/loxP), with the Pgr(cre) mouse model. Pgr(cre/+) Foxa2(loxP/loxP) mice showed significantly reduced fertility. Analysis of the uterus on Day 5.5 of pregnancy showed disrupted blastocyst implantation. Pgr(cre/+) Foxa2(loxP/loxP) mice also showed a severe impairment of the uterus to respond to the artificial induction of the decidual response. Morphological examination of the uteri of these mice showed a severe reduction in the number of endometrial glands. The loss of endometrial glands resulted in the reduction of leukemia inhibitory factor (Lif) expression. The lack of a decidual response could be partially rescued by an intrauterine injection of LIF before the initiation of the decidual response. This analysis demonstrates that Foxa2 regulates endometrial gland development and that mice with a loss of endometrial glands cannot support implantation in part due to the loss of LIF, which is a requisite for fertility in the mouse.
Biology of Reproduction 09/2010; 83(3):396-403. · 4.01 Impact Factor
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ABSTRACT: Previous work has identified Indian hedgehog (Ihh) as a major mediator of progesterone signaling during embryo implantation. Ihh acts through its downstream effector smoothened (Smo) to activate the GLI family of transcription factors. In order to gain a better understanding of Ihh action during embryo implantation, we expressed a Cre-recombinase-dependent constitutively activated SMO in the murine uterus using the Pgr(tm2(cre)Lyd) (PR(cre)) mouse model [Pgr(tm2(cre)Lyd+)Gt(ROSA)26Sor(tm1(Smo/EYFP)Amc)(+) (PR(cre/+)SmoM2(+))]. Female PR(cre/+)SmoM2(+) mice were infertile. They exhibited normal serum progesterone levels and normal ovulation, but their ova failed to be fertilized in vivo and their uterus failed to undergo the artificially induced decidual response. Examination of the PR(cre/+)SmoM2(+) uteri revealed numerous features such as uterine hypertrophy, the presence of a stratified luminal epithelial cell layer, a reduced number of uterine glands, and an endometrial stroma that had lost its normal morphologic characteristics. Microarray analysis of 3-mo-old PR(cre/+)SmoM2(+) uteri demonstrated a chondrocytic signature and confirmed that constitutive activation of PR(cre/+)SmoM2(+) increased extracellular matrix production. Thus, constitutive activation of Smo in the mouse uterus alters postnatal uterine differentiation which interferes with early pregnancy. These results provide new insight into the role of Hedgehog signaling during embryo implantation.
Biology of Reproduction 05/2010; 82(5):991-9. · 4.01 Impact Factor
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ABSTRACT: Conditional ablation of Indian hedgehog (Ihh) in the murine uterus results in mice that are sterile because of defects in embryo implantation. We performed microarray analysis on these mice at the time point at which the Ihh target genes are induced by the administration of exogenous hormone to mimic Day 3.5 of pregnancy. This analysis identified 863 genes altered by the conditional ablation of Ihh. Of these, genes that regulated the cell cycle were overrepresented. In addition, genes involved in epidermal growth factor (EGF) and estrogen (E2) signaling were found to be deregulated upon Ihh ablation. Furthermore, upon conditional ablation of Ihh, 15-mo-old mice exhibited hallmarks of estrogenized uteri, such as cystically dilated glands and hyalinized stroma. Thus, Ihh regulates embryo implantation by having an impact on the cell cycle, EGF signaling, and E2 signaling.
Biology of Reproduction 04/2010; 82(4):783-90. · 4.01 Impact Factor
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ABSTRACT: Endometrial cancer is the most common gynecological cancer. Estrogen-dependent endometrioid carcinoma is the most common type of endometrial cancer, and alterations in the expression of PTEN and K-ras have been associated with this disease. To study the roles of Pten and K-ras in endometrial cancer, we generated Pten ablation and oncogenic K-ras mutation in progesterone receptor positive cells (PR(cre/+)Pten(f/f)K-ras(G12D)). Double mutant mice dramatically accelerated the development of endometrial cancer compared to a single mutation of either gene. Histological analysis showed that all of the 1-month old double mutant female mice developed endometrial cancer with myometrial invasion. The expression of PR was downregulated in double mutant mice compared to a single mutation of either gene which resulted in decreased suppression of estrogen signaling. Therefore, these results suggest a synergistic effect of dysregulation of the Pten and K-ras signaling pathways during endometrial tumorigenesis.
Journal of Oncology 01/2010; 2010:139087.
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Jae-Wook Jeong,
Hee Sun Lee, Kevin Y Lee,
Lisa D White,
Russell R Broaddus,
Yu-Wen Zhang,
George F Vande Woude,
Linda C Giudice,
Steven L Young,
Bruce A Lessey,
Sophia Y Tsai,
John P Lydon,
Francesco J DeMayo
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ABSTRACT: Normal endometrial function requires a balance of progesterone (P4) and estrogen (E2) effects. An imbalance caused by increased E2 action and/or decreased P4 action can result in abnormal endometrial proliferation and, ultimately, endometrial adenocarcinoma, the fourth most common cancer in women. We have identified mitogen-inducible gene 6 (Mig-6) as a downstream target of progesterone receptor (PR) and steroid receptor coactivator (SRC-1) action in the uterus. Here, we demonstrate that absence of Mig-6 in mice results in the inability of P4 to inhibit E2-induced uterine weight gain and E2-responsive target genes expression. At 5 months of age, the absence of Mig-6 results in endometrial hyperplasia. Ovariectomized Mig-6(d/d) mice exhibit this hyperplastic phenotype in the presence of E2 and P4 but not without ovarian hormone. Ovariectomized Mig-6(d/d) mice treated with E2 developed invasive endometrioid-type endometrial adenocarcinoma. Importantly, the observation that endometrial carcinomas from women have a significant reduction in MIG-6 expression provides compelling support for an important growth regulatory role for Mig-6 in the uterus of both humans and mice. This demonstrates the Mig-6 is a critical regulator of the response of the endometrium to E2 in regulating tissue homeostasis. Since Mig-6 is regulated by both PR and SRC-1, this identifies a PR, SRC-1, Mig-6 regulatory pathway that is critical in the suppression of endometrial cancer.
Proceedings of the National Academy of Sciences 06/2009; 106(21):8677-82. · 9.68 Impact Factor
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ABSTRACT: The role of the p160 steroid receptor coactivator 2 (SRC-2) in the regulation of uterine function and progesterone (P4) signaling was investigated by determining the expression pattern of SRC-2 in the murine uterus during pregnancy and the impact of SRC-2 ablation on uterine function and global uterine gene expression in response to progesterone. SRC-2 is expressed in the endometrial luminal and glandular epithelium from pregnancy d 0.5. SRC-2 is then expressed in the endometrial stroma on pregnancy d 2.5-3.5. Once the embryo is implanted, SRC-2 is expressed in the endometrial stromal cells in the secondary decidual zone. This compartmental expression of SRC-2 can be mimicked by treatment of ovariectomized mice with estrogen and P4. Ablation of SRC-2 in the uterus resulted in a significant reduction in the ability of the uterus to undergo a hormonally induced decidual reaction. Microarray analysis of RNA from uteri of wild-type and SRC-2(-/-) mice treated with vehicle or P4 showed that SRC-2 was involved in the ability of progesterone to repress specific genes. This microarray analysis also revealed that the uteri of SRC-2(-/-) mice showed alterations in genes involved in estrogen receptor, Wnt, and bone morphogenetic protein signaling. This analysis indicates that SRC-2 regulates uterine function by modulating the regulation of developmentally important signaling molecules and the ability of P4 to repress specific genes.
Endocrinology 10/2007; 148(9):4238-50. · 4.46 Impact Factor
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ABSTRACT: The process of implantation, necessary for nearly all viviparous birth, consists of tightly regulated reactions including apposition of the blastocyst, attachment to the uterine epithelium and decidualization of the uterine stroma. In order for implantation to be successful, a reciprocal interaction between an implantation competent blastocyst and receptive uterus must be achieved. A more thorough understanding of the molecular mechanisms that regulate uterine receptivity and implantation is of clinical relevance to correct implantation failure and improve pregnancy rates. As molecular methodologies have evolved in recent times, the use of in vivo models to elucidate the molecular mechanisms involved in implantation has increased. The mouse has emerged as a powerful model to investigate implantation owing to the ability to control uterine physiology through exogenous stimuli, and more recently, the ability to manipulate gene expression. This review describes the evolution of the mouse as a model for understanding uterine implantation, including exciting new advances in this field, and describes a novel genetic pathway that can be elucidated from these models.
Trends in Endocrinology and Metabolism 09/2007; 18(6):234-9. · 8.11 Impact Factor
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ABSTRACT: The process of implantation, necessary for all viviparous birth, consists of tightly regulated events, including apposition of the blastocyst, attachment to the uterine lumen, and differentiation of the uterine stroma. In rodents and primates the uterine stroma undergoes a process called decidualization. Decidualization, the process by which the uterine endometrial stroma proliferates and differentiates into large epithelioid decidual cells, is critical to the establishment of fetal-maternal communication and the progression of implantation. The role of bone morphogenetic protein 2 (Bmp2) in regulating the transformation of the uterine stroma during embryo implantation in the mouse was investigated by the conditional ablation of Bmp2 in the uterus using the (PR-cre) mouse. Bmp2 gene ablation was confirmed by real-time PCR analysis in the PR-cre; Bmp2fl/fl (termed Bmp2d/d) uterus. While littermate controls average 0.9 litter of 6.2+/-0.7 pups per month, Bmp2d/d females are completely infertile. Analysis of the infertility indicates that whereas embryo attachment is normal in the Bmp2d/d as in control mice, the uterine stroma is incapable of undergoing the decidual reaction to support further embryonic development. Recombinant human BMP2 can partially rescue the decidual response, suggesting that the observed phenotypes are not due to a developmental consequence of Bmp2 ablation. Microarray analysis demonstrates that ablation of Bmp2 leads to specific gene changes, including disruption of the Wnt signaling pathway, Progesterone receptor (PR) signaling, and the induction of prostaglandin synthase 2 (Ptgs2). Taken together, these data demonstrate that Bmp2 is a critical regulator of gene expression and function in the murine uterus.
Molecular and Cellular Biology 09/2007; 27(15):5468-78. · 5.53 Impact Factor
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ABSTRACT: Members of the steroid receptor coactivator (SRC) family, which include SRC-1 (NcoA-1/p160), SRC-2(TIF2/GRIP1/NcoA-2) and SRC-3(pCIP/RAC3/ACTR/pCIP/ AIB1/TRAM1), are critical mediators of steroid receptor action. Gene ablation studies previously identified SRC-1 and SRC-2 as being involved in the control of energy homeostasis. A more precise identification of the molecular pathways regulated by these coactivators is crucial for understanding the role of steroid receptor coactivators in the control of energy homeostasis and obesity. A genomic approach using microarray analysis was employed to identify the subsets of genes that are altered in the livers of SRC-1-/-, SRC-2-/-, and SRC-3-/- mice. Microarray analysis demonstrates that gene expression changes are specific and nonoverlapping for each SRC member in the liver. The overall pattern of altered gene expressions in the SRC-1-/- mice was up-regulation, whereas SRC-2-/- mice showed an overall down-regulation. Several key regulatory enzymes of energy metabolism were significantly altered in the liver of SRC-2-/- mice, which are consistent with the prior observation that SRC-2-/- mice have increased energy expenditure. This study demonstrates that the molecular targets of SRC-2 regulation in the murine liver stimulate fatty acid degradation and glycolytic pathway, whereas fatty acid, cholesterol, and steroid biosynthetic pathways are down-regulated.
Molecular Endocrinology 06/2006; 20(5):1138-52. · 4.54 Impact Factor
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ABSTRACT: Progesterone (P4) acting through its cognate receptor, the progesterone receptor (PR), plays an important role in uterine physiology. The PR knockout (PRKO) mouse has demonstrated the importance of the P4-PR axis in the regulation of uterine function. To define the molecular pathways regulated by P4-PR in the mouse uterus, Affymetrix MG U74Av2 oligonucleotide arrays were used to identify alterations in gene expression after acute and chronic P4 treatments. PRKO and wild-type mice were ovariectomized and then treated with vehicle or 1 mg P4 every 12 h. Mice were killed either 4 h after the first injection (acute P4 treatment) or after the fourth injection of P4 (chronic P4 treatment). At the genomic level, the major change in gene expression after acute P4 treatment was an increase in the expression of 55 genes. Conversely, the major change in gene expression after chronic P4 treatment was an overall reduction in the expression of 102 genes. In the analysis, retinoic acid metabolic genes, cytochrome P 450 26a1 (Cyp26a1), alcohol dehydrogenase 5, and aldehyde dehydrogenase 1a1 (Aldh1a1); kallikrein genes, Klk5 and Klk6; and specific transcription factors, GATA-2 and Cited2 [cAMP-corticosterone-binding protein/p300-interacting transactivator with glutamic acid (E) and aspartic acid (D)-rich tail], were validated as regulated by the P4-PR axis. Identification and analysis of these responsive genes will help define the role of PR in regulating uterine biology.
Endocrinology 09/2005; 146(8):3490-505. · 4.46 Impact Factor
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ABSTRACT: Implantation is an intricately timed event necessary in the process of viviparous birth that allows mammals to nourish and protect their young during early development. Human implantation begins when the blastocyst both assumes a fixed position in the uterus and establishes a more intimate relationship with the endometrium. Due to the impracticalities of studying implantation in humans, animal models are necessary to decipher the molecular and mechanical events of this process. This review will discuss the differences in implantation between different animal models and describe how these differences can be utilized to investigate discrete implantation stages. In addition, factors that have been shown to be involved in implantation in the human and other various animal models including growth factors, cytokines, modulators of cell adhesion, and developmental factors will be discussed, and examples from each will be given.
Reproduction (Cambridge, England) 01/2005; 128(6):679-95. · 3.09 Impact Factor
