المؤلفون: Hye Ryun Kim, Mira Park, Yeon Sun Kim, Haengseok Song, Jung Ah Yoon, Dong-Won Seol, Dong Ryul Lee, Seung Chel Yang, Sang Woo Lyu, Jin Hyun Jun, Hyunjung Jade Lim

المصدر: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 32(3)

مصطلحات موضوعية: 0301 basic medicine, endocrine system, medicine.medical_specialty, Stromal cell, medicine.drug_class, media_common.quotation_subject, Uterus, Embryonic Development, Biology, Biochemistry, Epithelium, 03 medical and health sciences, Mice, Pregnancy, Internal medicine, Progesterone receptor, Genetics, medicine, Animals, Embryo Implantation, Molecular Biology, Ovulation, Cells, Cultured, media_common, Epithelial cell differentiation, Early Growth Response Protein 1, Mice, Knockout, Mice, Inbred ICR, Decidualization, Embryo, Estrogens, Cell biology, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Gene Expression Regulation, Receptors, Estrogen, Estrogen, Female, Receptors, Progesterone, Biotechnology, Signal Transduction

الوصف: The harmonized actions of ovarian E2 and progesterone (P4) regulate the proliferation and differentiation of uterine cells in a spatiotemporal manner. Imbalances between these hormones often lead to infertility and gynecologic diseases. Whereas numerous factors that are involved in P4 signaling have been identified, few local factors that mediate E2 actions in the uterus have been revealed. Here, we demonstrate that estrogen induces the transcription factor, early growth response 1 ( Egr1), to fine-tune its actions in uterine epithelial cells (ECs) that are responsible for uterine receptivity for embryo implantation. In the presence of exogenous gonadotrophins, ovulation, fertilization, and embryonic development normally occur in Egr1-/- mice, but these animals experience the complete failure of embryo implantation with reduced artificial decidualization. Although serum levels of E2 and P4 were comparable between Egr1+/+ and Egr1-/- mice on d 4 of pregnancy, aberrantly reduced levels of progesterone receptor in Egr1-/- uterine ECs caused enhanced E2 activity and impaired P4 response. Ultrastructural analyses revealed that Egr1-/- ECs are not fully able to provide proper uterine receptivity. Uterine mRNA landscapes in Egr1-/- mice revealed that EGR1 controls the expression of a subset of E2-regulated genes. In addition, P4 signaling was unable to modulate estrogen actions, including those that are involved in cell-cycle progression, in ECs that were deficient in EGR1. Furthermore, primary coculture of Egr1-/- ECs with Egr1+/+ stromal cells, and vice versa, supported the notion that Egr1 is required to modulate E2 actions on ECs to prepare the uterine environment for embryo implantation. In contrast to its role in ECs, loss of Egr1 in stroma significantly reduced stromal cell proliferation. Collectively, our results demonstrate that E2 induces EGR1 to streamline its actions for the preparation of uterine receptivity for embryo implantation in mice.-Kim, H.-R., Kim, Y. S., Yoon, J. A., Yang, S. C., Park, M., Seol, D.-W., Lyu, S. W., Jun, J. H., Lim, H. J., Lee, D. R., Song, H. Estrogen induces EGR1 to fine-tune its actions on uterine epithelium by controlling PR signaling for successful embryo implantation.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::10d1806b2e08f3c61968941816733e49Test
https://pubmed.ncbi.nlm.nih.gov/29092905Test

المؤلفون: Dong Ryul Lee, Hyunjung Jade Lim, Jung Ah Yoon, Yeon Sun Kim, Hye Ryun Kim, Hyejin Shin, Seok-Ho Hong, Haengseok Song, Sang Woo Lyu

المصدر: Reproductive toxicology (Elmsford, N.Y.). 50

مصطلحات موضوعية: endocrine system, medicine.medical_specialty, medicine.drug_class, MAP Kinase Signaling System, Estrogen receptor, Biology, Toxicology, Mice, Phenols, Internal medicine, Progesterone receptor, medicine, Animals, Benzhydryl Compounds, Receptor, Extracellular Signal-Regulated MAP Kinases, Protein kinase B, Early Growth Response Protein 3, Estrogen receptor beta, Progesterone, Early Growth Response Protein 1, Mice, Inbred ICR, Dose-Response Relationship, Drug, urogenital system, Uterus, Decidualization, Estrogens, Endocrinology, Receptors, Estrogen, Estrogen, Female, Estrogen receptor alpha, Proto-Oncogene Proteins c-akt, hormones, hormone substitutes, and hormone antagonists

الوصف: Coordinate actions of ovarian estrogen (E2) and progesterone (P4) via their own receptors are critical for establishing uterine receptivity for embryo implantation in the uterus. E2 regulates expression of an array of genes to mediate its major actions on heterogeneous uterine cell types. Here we have investigated regulatory mechanism(s) of E2 and bisphenol A (BPA), an endocrine disruptor with potent estrogenic activity on expression of early growth response 1 (Egr1), a zinc finger transcription factor that regulates cell growth, differentiation and apoptosis in the uterus. Egr1 was rapidly and transiently induced by E2 and BPA mainly in stromal cells via nuclear estrogen receptor (ER)-ERK1/2 pathway. ICI 182,780, an ER antagonist, effectively inhibited their actions on EGR1 expression following ERK1/2 phosphorylation. Administration of pharmacological inhibitors for ERK1/2, but not AKT significantly blocked EGR1 expression induced by E2 and BPA. P4 effectively dampened action(s) of E2 and BPA on Egr1 expression via nuclear progesterone receptor. Its antagonistic effects were partially interfered with RU486 pretreatment. Interestingly, EGR1 is specifically induced in stromal cells surrounding implanting blastocyst. Collectively, our results show that through nuclear ER-dependent ERK1/2 phosphorylation, not only E2 but also endocrine disruptors with estrogenic activity such as BPA rapidly and transiently induce Egr1 which may be important for embryo implantation and decidualization in mouse uterus.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e2fa80a436eae1846ed0db5f2c927874Test
https://pubmed.ncbi.nlm.nih.gov/25461906Test

المؤلفون: James M. Trzaskos, Peggy Scherle, Hyunjung Jade Lim, Wen-ge Ma, Sudhansu K. Dey

المصدر: Journal of Biological Chemistry. 275:37086-37092

مصطلحات موضوعية: MAPK/ERK pathway, medicine.medical_specialty, Intracrine, Stromal cell, MEK inhibitor, Decidualization, Prostacyclin, Cell Biology, Biology, Biochemistry, Endocrinology, Internal medicine, medicine, Signal transduction, Kinase activity, Molecular Biology, medicine.drug

الوصف: The infertility phenotype of cyclooxygenase-2 (Cox-2)-deficient female mice establishes the important role of Cox-2 in pregnancy. Cox-2 deficiency results in defective ovulation, fertilization, implantation, and decidualization; the latter of which can be restored in part by the prostacyclin analog carbaprostacyclin. Uterine Cox-2 expression during early pregnancy shows distinct localization and kinetics in the uterine luminal epithelium and underlying stromal cells, suggesting that expression is tightly regulated. Several intracellular signaling cascades including ERK, p38, and JNK are implicated in vitro as critical components of regulated Cox-2 expression in response to mitogens, growth factors, and cytokines. We investigated the involvement of these signaling pathways during Cox-2 induction in vivo by monitoring uterine kinase activity after intraluminal application of a deciduogenic stimulus. Our results show that the ERK and p38 pathways are activated in uterine preparations as early as 5-min post-stimulation. ERK activation was sustained for several hours with a return to baseline levels by 4 h. p38 activation was rapid with a peak at 5-min post-stimulation and returned to near baseline levels after 45 min. Systemic administration of a MEK inhibitor completely inhibited ERK activation, but did not affect early (2 h) luminal epithelial or late (24 h) stromal Cox-2 expression and only modestly affected decidualization. In contrast, administration of a p38 inhibitor modestly inhibited early Cox-2 expression in the luminal epithelium, while dramatically diminishing late stromal expression. In parallel, induced stromal peroxisomal proliferator activated receptor-δ (PPARδ) expression is blunted by p38 inhibition. p38 inhibition also significantly inhibited decidualization. These results suggest that p38, but not ERK, activation is required for induced Cox-2 and PPARδ expression during decidualization. In addition, inhibition of p38 led to decreased decidualization suggesting that an intracrine prostanoid pathway consisting of Cox-2, prostacyclin, and PPARδ is required for maintenance of early pregnancy.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::845ce8ffda441a9d977d330bef5d6f7fTest
https://doi.org/10.1074/jbc.m006168200Test

المؤلفون: Jason D. Morrow, Bibhash C. Paria, Sudhansu K. Dey, Rajnish A. Gupta, Hyunjung Jade Lim, James M. Trzaskos, Raymond N. DuBois, David E. Moller, Wen Ge Ma

المصدر: Genes & Development. 13:1561-1574

مصطلحات موضوعية: medicine.medical_specialty, Transcription, Genetic, Receptors, Retinoic Acid, Receptors, Prostaglandin, Gene Expression, Receptors, Cytoplasmic and Nuclear, Prostacyclin, macromolecular substances, Biology, Receptors, Epoprostenol, Endometrium, Mice, Cytochrome P-450 Enzyme System, Genes, Reporter, Internal medicine, Decidua, Genetics, medicine, Animals, Embryo Implantation, Nuclear protein, Luciferases, Receptor, Transcription factor, Cell Nucleus, Mice, Knockout, Nuclear Proteins, food and beverages, Decidualization, Epoprostenol, Cell biology, Intramolecular Oxidoreductases, Isoenzymes, Retinoid X Receptors, medicine.anatomical_structure, Endocrinology, Nuclear receptor, Cyclooxygenase 2, Prostaglandin-Endoperoxide Synthases, Female, lipids (amino acids, peptides, and proteins), Dimerization, Transcription Factors, Research Paper, Developmental Biology, medicine.drug

الوصف: We have demonstrated previously that cyclo-oxygenase-2 (COX2), the rate-limiting enzyme in the biosynthesis of prostaglandins (PGs), is essential for blastocyst implantation and decidualization. However, the candidate PG(s) that participates in these processes and the mechanism of its action remain undefined. Using COX2-deficient mice and multiple approaches, we demonstrate herein that COX2-derived prostacyclin (PGI2) is the primary PG that is essential for implantation and decidualization. Several lines of evidence suggest that the effects of PGI2 are mediated by its activation of the nuclear hormone receptor PPARdelta, demonstrating the first reported biologic function of this receptor signaling pathway.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::931d58b1e3d405e11edf388a69eb4121Test
https://doi.org/10.1101/gad.13.12.1561Test

المؤلفون: Liang Ma, Richard L. Maas, Sudhansu K. Dey, Hyunjung Jade Lim, Wen-ge Ma

المصدر: Molecular Endocrinology. 13:1005-1017

مصطلحات موضوعية: Male, medicine.medical_specialty, Stromal cell, Ovariectomy, Genes, myc, Uterus, Biology, Dinoprostone, Mice, Endocrinology, Stroma, Pregnancy, Internal medicine, Decidua, medicine, Animals, Receptors, Prostaglandin E, Embryo Implantation, Receptor, Molecular Biology, Progesterone, Homeodomain Proteins, Regulation of gene expression, Tissue Inhibitor of Metalloproteinase-2, Estradiol, Cell growth, Estrogen Receptor alpha, Metalloendopeptidases, Decidualization, General Medicine, Mice, Mutant Strains, Epithelium, Cell biology, DNA-Binding Proteins, Isoenzymes, Homeobox A10 Proteins, medicine.anatomical_structure, Gene Expression Regulation, Receptors, Estrogen, Cyclooxygenase 2, Gelatinases, Prostaglandin-Endoperoxide Synthases, Matrix Metalloproteinase 2, Female, Stromal Cells, Receptors, Progesterone, Cell Division

الوصف: Hoxa-10 is an AbdominalB-like homeobox gene that is expressed in the developing genitourinary tract during embryogenesis and in the adult uterus during early pregnancy. Null mutation of Hoxa-10 in the mouse causes both male and female infertility. Defective implantation and decidualization resulting from the loss of maternal Hoxa-10 function in uterine stromal cells is the cause of female infertility. However, the mechanisms by which Hoxa-10 regulates these uterine events are unknown. We have identified two potential mechanisms for these uterine defects in Hoxa-10(-/-) mice. First, two PGE2 receptor subtypes, EP3 and EP4, are aberrantly expressed in the uterine stroma in Hoxa-10(-/-) mice, while expression of several other genes in the stroma (TIMP-2, MMP-2, ER, and PR) and epithelium (LIF, HB-EGF, Ar, and COX-1) are unaffected before implantation. Further, EP3 and EP4 are inappropriately regulated by progesterone (P4) in the absence of Hoxa-10, while PR, Hoxa-11 and c-myc, three other P4-responsive genes respond normally. These results suggest that Hoxa-10 specifically mediates P4 regulation of EP3 and EP4 in the uterine stroma. Second, since Hox genes are implicated in local cell proliferation, we also examined steroid-responsive uterine cell proliferation in Hoxa-10(-/-) mice. Stromal cell proliferation in mutant mice in response to P4 and 17beta-estradiol (E2 was significantly reduced, while epithelial cell proliferation was normal in response to E2. These results suggest that stromal cell responsiveness to P4 with respect to cell proliferation is impaired in Hoxa-10(-/-) mice, and that Hoxa-10 is involved in mediating stromal cell proliferation. Collectively, these results suggest that Hoxa-10 mutation causes specific stromal cell defects that can lead to implantation and decidualization defects apparently without perturbing epithelial cell functions.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0b1d6d564a86f447a29009a3b35d368aTest
https://doi.org/10.1210/mend.13.6.0284Test

المؤلفون: Sudhansu K. Dey, Hyunjung Jade Lim

المصدر: Endocrinology. 138:4599-4606

مصطلحات موضوعية: endocrine system, medicine.medical_specialty, urogenital system, Prostaglandin E2 receptor, Uterus, Decidualization, In situ hybridization, Biology, Epithelium, Endocrinology, medicine.anatomical_structure, Internal medicine, Gene expression, medicine, lipids (amino acids, peptides, and proteins), Signal transduction, Receptor

الوصف: Among the PGs, PGE2 is considered especially important for implantation and decidualization. Four major PGE2 receptor subtypes, EP1, EP2, EP3, and EP4, mediate various PGE2 effects via their coupling to distinct signaling pathways. Previously, we have shown that the EP1, EP3, and EP4 genes are expressed in the periimplantation mouse uterus in a spatio-temporal manner, suggesting compartmentalized actions of PGE2 during this period. In this study, we examined the expression of the EP2 gene in the mouse uterus during the periimplantation period (days 1-8) and during experimentally induced progesterone (P4)-maintained delayed implantation and its resumption by 17beta-estradiol (E2). We also examined its regulation in the uterus by ovarian steroid hormones. Our results establish that EP2 messenger RNA (mRNA) is expressed exclusively in the luminal epithelium primarily on day 4 (the day of implantation) and day 5 (early implantation) of pregnancy. In (P4)-maintained delayed implanting mice, EP2 mRNA was present in the luminal epithelium, and the expression was further enhanced regardless of the location of the blastocysts after reinitiation of implantation. This observation suggests little or no embryonic influence in regulating EP2 expression and, instead, shows its regulation by P4 and E2. Indeed, treatment with E2 and/or P4 exhibited unique regulation of this gene. The treatment of adult ovariectomized mice with E2 down-regulated the basal levels of EP2 mRNA, whereas that with P4 up-regulated its levels in the luminal epithelium. The up-regulation of EP2 mRNA levels by P4 was further augmented by superimposition of the E2 treatment, suggesting a synergistic interaction between E2 and P4 in regulating this gene in the uterus. Collectively, the results suggest that EP2 could be a potential mediator of PGE2 actions in regulating luminal epithelial differentiation and serve as a marker for uterine receptivity for implantation.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::bf1cff19792f70cfd84af5cad2a071a7Test
https://doi.org/10.1210/endo.138.11.5528Test

المؤلفون: Robert Langenbach, James M. Trzaskos, Hyunjung Jade Lim, Joseph E. Dinchuk, Sudhansu K. Dey, Bibhash C. Paria, Sanjoy K. Das

المصدر: Cell. 91(2):197-208

مصطلحات موضوعية: Gene isoform, Ovulation, medicine.medical_specialty, Cholera Toxin, media_common.quotation_subject, PTGS1, General Biochemistry, Genetics and Molecular Biology, Mice, Pregnancy, Internal medicine, medicine, Decidua, Animals, Receptors, Prostaglandin E, Embryo Implantation, RNA, Messenger, Enzyme Inhibitors, Pseudopregnancy, Receptor, media_common, Mice, Knockout, biology, Dose-Response Relationship, Drug, Biochemistry, Genetics and Molecular Biology(all), Uterus, Decidualization, Membrane Proteins, medicine.disease, Epoprostenol, Isoenzymes, Mice, Inbred C57BL, Endocrinology, Blastocyst, Gene Expression Regulation, Peroxidases, Cyclooxygenase 2, Prostaglandin-Endoperoxide Synthases, Fertilization, biology.protein, Cyclooxygenase 1, Female, Steroids, Cyclooxygenase, Platelet Aggregation Inhibitors, Hormone

الوصف: Cyclooxygenase (COX) is the rate-limiting enzyme in the synthesis of prostaglandins (PGs) and exists in two isoforms, COX-1 and COX-2. In spite of long-standing speculation, definitive roles of PGs in various events of early pregnancy remain elusive. We demonstrate herein that the targeted disruption of COX-2, but not COX-1, in mice produces multiple failures in female reproductive processes that include ovulation, fertilization, implantation, and decidualization. Using multiple approaches, we conclude that these defects are the direct result of target organ–specific COX-2 deficiency but are not the result of deficiency of pituitary gonadotropins or ovarian steroid hormones, or reduced responsiveness of the target organs to their respective hormones.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::036c58803e437635f111932c9c63b64fTest

المؤلفون: Hyunjung Jade Lim, Haengseok Song, Kyuyong Han

المصدر: Reproduction (Cambridge, England). 133(2)

مصطلحات موضوعية: Embryology, medicine.medical_specialty, Gene Expression, Gestational Age, In situ hybridization, Fertilization in Vitro, Biology, Leukemia Inhibitory Factor, Mice, Endocrinology, Pregnancy, Internal medicine, Gene expression, medicine, Decidua, Animals, Blastocyst, Embryo Implantation, RNA, Messenger, Pseudopregnancy, In Situ Hybridization, Progesterone, Cell Proliferation, Cell growth, Uterus, Obstetrics and Gynecology, Decidualization, Embryo, Cell Biology, medicine.disease, Embryo Transfer, eye diseases, Embryo transfer, medicine.anatomical_structure, Reproductive Medicine, Autoradiography, Female

الوصف: We previously showed that blastocyst can initiate implantation beyond the normal ‘window’ of uterine receptivity on day 5 of pregnancy and pseudopregnancy (PSP) in mice. In this study, we investigated whether uterine receptivity for blastocyst implantation can be further extended on day 6 of PSP and the role of progesterone (P4) on this event. Embryo transfers, experimentally induced decidualization,in situhybridization and [3H]thymidine incorporation were performed. Blastocysts initiate attachment reaction within 48 h when transferred on day 5, but not on day 6 of PSP. Likewise, decidualization reaction occurred on days 4 and 5 of PSP, but completely failed on day 6. However, P4supplementation partially retains uterine receptivity for blastocyst implantation and decidualization on day 6 of PSP. In addition, certain indicators of uterine receptivity, such as cell proliferation profile and expression patterns of implantation-related genes were similarly observed on days 4 and 5 of PSP, but not on day 6. Consistent with embryo transfer and decidualization, exogenous administration of P4partially restores these indicators on day 6 of PSP. We concluded that critical physiological changes occur between days 4 and 5 of PSP, leading to uterine non-receptivity on day 6, but P4is able to extend the uterine receptivity through day 6.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1f5dd63d4290592bf05bf1f06baa8da5Test
https://pubmed.ncbi.nlm.nih.gov/17307916Test

المؤلفون: Ichiro Satokata, Gail V. Benson, Sudhansu K. Dey, Hyunjung Jade Lim, Richard L. Maas, Bibhash C. Paria

المصدر: Development (Cambridge, England). 122(9)

مصطلحات موضوعية: Male, medicine.medical_specialty, Mutant, Uterus, Mice, Transgenic, Biology, Genitalia, Male, Embryonic and Fetal Development, Mice, Pregnancy, Internal medicine, medicine, Morphogenesis, Animals, Embryo Implantation, Molecular Biology, In Situ Hybridization, Progesterone, Homeodomain Proteins, Wild type, Genes, Homeobox, Decidualization, Genitalia, Female, Epididymis, Embryo Transfer, Embryo transfer, DNA-Binding Proteins, Endocrinology, medicine.anatomical_structure, Fertility, Homeobox A10 Proteins, Phenotype, Infertility, Embryo Loss, Oviduct, Female, Homeotic gene, Developmental Biology

الوصف: The establishment of a receptive uterine environment is critical for embryonic survival and implantation. One gene that is expressed in the uterus during the peri-implantation period in mice and is required for female fertility is the homeobox gene Hoxa-10. Here we characterize the periimplantation defects in Hoxa-10 mutant females and investigate functions of Hoxa-10 in the uterine anlage during morphogenesis and in the adult uterus during pregnancy. Examination of pregnancy in Hoxa-10 mutant females has revealed failure of implantation as well as resorption of embryos in the early postimplantation period. Morphologic analysis of the mutant uterus has demonstrated homeotic transformation of the proximal 25% into oviduct. Histology and molecular markers confirm this anterior transformation. Furthermore, in situ hybridization shows that this region coincides with the anterior limit of embryonic Hoxa-10 expression in the urogenital ducts and a parallel transformation is observed in Hoxa-10 mutant males at the junction of the epididymis and ductus deferens. Female fertility could be compromised by either the homeotic transformation or the absence of Hoxa-10 function in the adult during pregnancy. To distinguish between these two potential mechanisms of infertility, wildtype blastocysts were transferred into mutant uteri distal to the transformed region on day 2.5 of pseudopregnancy. This procedure did not rescue the phenotype, suggesting that adult uterine expression of Hoxa-10 is required during pregnancy. Moreover, when implantation was experimentally delayed, homozygous uteri were able to support survival of blastocysts comparable to wild-type controls, indicating that the requirement for Hoxa-10 is intrinsic to implantation. While expression of LIF and HB-EGF appears unaffected in the mutant uteri, a decrease is observed in the intensity and number of blue dye reactions, an indicator of increased vascular permeability in response to implantation. In addition, mutant uteri exhibited decreased decidualization in response to artificial stimuli. These results show that Hoxa-10 is required during morphogenesis for proper patterning of the reproductive tract and in the adult uterus for peri-implantation events.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::02aacb48fbd4b8b573e0a916415c7d4dTest
https://pubmed.ncbi.nlm.nih.gov/8787743Test