RESUMO
Decidualization is an essential process of maternal endometrial stromal cells to support pregnancy. Although it is known that enhanced glucose influx is critical for decidualization, the underlying mechanism in regulating glucose metabolism in decidua remains insufficiently understood. Here, we demonstrate that aerobic glycolysis-related genes and factors are all substantially induced during decidualization, indicating the existence of Warburg-like glycolysis in decidua. In vitro, progesterone activates hypoxia-inducible factor 1α (Hif1α) and c-Myc through Pi3k-Akt signaling pathway to maintain aerobic glycolysis in decidualizing cells. Knocking down of pyruvate kinase M2 (Pkm2) attenuates the induction of decidual marker gene. Decidual formation in vivo is also impaired by glycolysis inhibitor 3-bromopyruvate. Besides, lactate exporter monocarboxylate transporter 4 (Mct4) is induced in newly formed decidual cells, whereas lactate importer Mct1 and proliferation marker Ki-67 are complementarily located in the surrounding undifferentiated cells, which are supposed to consume lactate for proliferation. Hif1α activation is required for lactate-dependent proliferation of the undifferentiated cells. Inhibition of lactate flux leads to compromised decidualization and decelerated lactate-dependent proliferation. In summary, we reveal that Warburg-like glycolysis and local lactate shuttle are activated in decidua and play important roles for supporting early pregnancy.
Assuntos
Endométrio/citologia , Glicólise , Ácido Láctico/metabolismo , Camundongos/fisiologia , Prenhez/fisiologia , Animais , Células Cultivadas , Endométrio/fisiologia , Feminino , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Gravidez , Progesterona/metabolismo , Células Estromais/citologia , Células Estromais/metabolismoRESUMO
Embryo implantation is a highly synchronized process between an activated blastocyst and a receptive uterus. Successful implantation relies on the dynamic interplay of estrogen and progesterone, but the key mediators underlying embryo implantation are not fully understood. Here we show that transcription factor early growth response 1 (Egr1) is regulated by estrogen as a downstream target through leukemia inhibitory factor (LIF) signal transducer and activator of transcription 3 (STAT3) pathway in mouse uterus. Egr1 is localized in the subluminal stromal cells surrounding the implanting embryo on day 5 of pregnancy. Estrogen rapidly, markedly, and transiently enhances Egr1 expression in uterine stromal cells, which fails in estrogen receptor α knock-out mouse uteri. STAT3 is phosphorylated by LIF and subsequently recruited on Egr1 promoter to induce its expression. Our results of Egr1 expression under induced decidualization in vivo and in vitro show that Egr1 is rapidly induced after deciduogenic stimulus. Egr1 knockdown can inhibit in vitro decidualization of cultured uterine stromal cells. Chromatin immunoprecipitation data show that Egr1 is recruited to the promoter of wingless-related murine mammary tumor virus integration site 4 (Wnt4). Collectively, our study presents for the first time that estrogen regulates Egr1 expression through LIF-STAT3 signaling pathway in mouse uterus, and Egr1 functions as a critical mediator of stromal cell decidualization by regulating Wnt4.
Assuntos
Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Implantação do Embrião , Estrogênios/metabolismo , Fator Inibidor de Leucemia/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteína Wnt4/metabolismo , Animais , Sequência de Bases , Imunoprecipitação da Cromatina , Primers do DNA , Proteína 1 de Resposta de Crescimento Precoce/genética , Feminino , Imunofluorescência , Técnicas de Silenciamento de Genes , Hibridização In Situ , Camundongos , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Thyroid disorders are relatively frequently observed in pregnant women. However, the impact of pregnancy on maternal thyroid has not been systematically evaluated. In the present study, using the rat as an animal model, we observed that the weight of maternal thyroid increased by about 18% in late pregnancy. To gain an insight into the molecular mechanisms, we took advantage of RNA-seq approaches to investigate global gene expression changes in the maternal thyroid. We identified a total of 615 differentially expressed genes, most of which (558 genes or 90.7%) were up-regulated in late pregnancy compared to the non-pregnant control. Gene ontology analysis showed that genes involved in cell cycle and metabolism were significantly enriched among up-regulated genes. Unexpectedly, pathway analysis revealed that expression levels for key components of the thyroid hormone synthesis pathway were not significantly altered. In addition, by examining of the promoter regions of up-regulated genes, we identified MAZ (MYC-associated zinc finger protein) and TFCP2 (transcription factor CP2) as two causal transcription factors. Our study contributes to an increase in the knowledge on the maternal thyroid adaptation to pregnancy.
Assuntos
Adaptação Fisiológica/genética , Regulação da Expressão Gênica , Glândula Tireoide/metabolismo , Transcriptoma , Animais , Sítios de Ligação , Análise por Conglomerados , Biologia Computacional/métodos , Feminino , Perfilação da Expressão Gênica , Anotação de Sequência Molecular , Motivos de Nucleotídeos , Tamanho do Órgão , Matrizes de Pontuação de Posição Específica , Gravidez , Ligação Proteica , Ratos , Transdução de Sinais , Glândula Tireoide/anatomia & histologia , Fatores de Transcrição/metabolismo , Ativação TranscricionalRESUMO
Embryo implantation into the maternal uterus is a crucial step for the successful establishment of mammalian pregnancy. Following the attachment of embryo to the uterine luminal epithelium, uterine stromal cells undergo steroid hormone-dependent decidualization, which is characterized by stromal cell proliferation and differentiation. The mechanisms underlying steroid hormone-induced stromal cell proliferation and differentiation during decidualization are still poorly understood. Ribonucleotide reductase, consisting of two subunits (RRM1 and RRM2), is a rate-limiting enzyme in deoxynucleotide production for DNA synthesis and plays an important role in cell proliferation and tumorgenicity. Based on our microarray analysis, Rrm2 expression was significantly higher at implantation sites compared with interimplantation sites in mouse uterus. However, the expression, regulation, and function of RRM2 in mouse uterus during embryo implantation and decidualization are still unknown. Here we show that although both RRM1 and RRM2 expression are markedly induced in mouse uterine stromal cells undergoing decidualization, only RRM2 is regulated by progesterone, a key regulator of decidualization. Further studies showed that the induction of progesterone on RRM2 expression in stromal cells is mediated by the AKT/c-MYC pathway. RRM2 can also be induced by replication stress and DNA damage during decidualization through the ATR/ATM-CHK1-E2F1 pathway. The weight of implantation sites and deciduoma was effectively reduced by specific inhibitors for RRM2. The expression of decidual/trophoblast prolactin-related protein (Dtprp), a reliable marker for decidualization in mice, was significantly reduced in deciduoma and steroid-induced decidual cells after HU treatment. Therefore, RRM2 may be an important effector of progesterone signaling to induce cell proliferation and decidualization in mouse uterus.
Assuntos
Proliferação de Células/efeitos dos fármacos , Dano ao DNA , Progesterona/farmacologia , Ribonucleosídeo Difosfato Redutase/genética , Útero/efeitos dos fármacos , Animais , Western Blotting , Células Cultivadas , Decídua/citologia , Decídua/efeitos dos fármacos , Decídua/metabolismo , Fator de Transcrição E2F1/genética , Fator de Transcrição E2F1/metabolismo , Implantação do Embrião/efeitos dos fármacos , Implantação do Embrião/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Hidroxiureia/farmacologia , Masculino , Camundongos , Ovariectomia , Gravidez , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ribonucleosídeo Difosfato Redutase/metabolismo , Ribonucleotídeo Redutases/genética , Ribonucleotídeo Redutases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Fatores de Tempo , Útero/citologia , Útero/metabolismoRESUMO
The genetic factors underlying female infertility in humans are only partially understood. Here, we performed a genome-wide association study of female infertility in 25 inbred mouse strains by using publicly available SNP data. As a result, a total of four SNPs were identified after chromosome-wise multiple test correction. The first SNP rs29972765 is located in a gene desert on chromosome 18, about 72 kb upstream of Skor2 (SKI family transcriptional corepressor 2). The second SNP rs30415957 resides in the intron of Plce1 (phospholipase C epsilon 1). The remaining two SNPs (rs30768258 and rs31216810) are close to each other on chromosome 19, in the vicinity of Sorbs1 (sorbin and SH3 domain containing 1). Using quantitative RT-PCR, we found that Sorbs1 is highly expressed in the mouse uterus during embryo implantation. Knockdown of Sorbs1 by siRNA attenuates the induction of differentiation marker gene Prl8a2 (decidual prolactin-related protein) in an in vitro model of decidualization using mouse endometrial stromal cells, suggesting that Sorbs1 may be a potential candidate gene for female infertility in mice. Our results may represent an opportunity to further understand female infertility in humans.
Assuntos
Infertilidade Feminina/genética , Proteínas dos Microfilamentos/genética , Fosfoinositídeo Fosfolipase C/genética , Prolactina/genética , Animais , Diferenciação Celular/genética , Mapeamento Cromossômico , Decídua/metabolismo , Decídua/patologia , Implantação do Embrião/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Infertilidade Feminina/patologia , Íntrons/genética , Camundongos , Polimorfismo de Nucleotídeo Único , Útero/metabolismoRESUMO
Decidualization is a crucial process for successful embryo implantation and pregnancy in humans. Defects in decidualization during early pregnancy are associated with several pregnancy complications, such as pre-eclampsia, intrauterine growth restriction and recurrent pregnancy loss. However, the mechanism underlying decidualization remains poorly understood. In the present study, we performed a systematic analysis of decidualization-related genes using text mining. We identified 286 genes for humans and 287 genes for mice respectively, with an overlap of 111 genes shared by both species. Through enrichment test, we demonstrated that although divergence was observed, the majority of enriched gene ontology terms and pathways were shared by both species, suggesting that functional categories were more conserved than individual genes. We further constructed a decidualization-related protein-protein interaction network consisted of 344 nodes connected via 1,541 edges. We prioritized genes in this network and identified 12 genes that may be key regulators of decidualization. These findings would provide some clues for further research on the mechanism underlying decidualization.
Assuntos
Decídua/metabolismo , Animais , Mineração de Dados , Implantação do Embrião/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Camundongos , Gravidez , Mapas de Interação de Proteínas , Transdução de Sinais/genéticaRESUMO
The prevalence of diabetes is increasing worldwide with the trend of patients being young and creating a significant burden on health systems, including reproductive problems, but the effects of diabetes on embryo implantation are still poorly understood. Our study was to examine effects of diabetes on mouse embryo implantation, providing experimental basis for treating diabetes and its complications. Streptozotocin (STZ) was applied to induce type 1 diabetes from day 2 of pregnancy or pseudopregnancy in mice. Embryo transfer was used to analyze effects of uterine environment on embryo implantation. Our results revealed that the implantation rate is significantly reduced in diabetic mice compared to controls, and the change of uterine environment is the main reason leading to the decreased implantation rate. Compared to control, the levels of LIF and p-STAT3 are significantly decreased in diabetic mice on day 4 of pregnancy, and serum estrogen level is significantly higher. Estrogen stimulates LIF expression under physiological level, but the excessive estrogen inhibits LIF expression. LIF, progesterone or insulin supplement can rescue embryo implantation in diabetic mice. Our data indicated that the dysregulated LIF-STAT3 pathway caused by the high level of estrogen results in the impaired implantation in diabetic mice, which can be rescued by LIF, progesterone or insulin supplement.
RESUMO
Receptivity is a limited time in which uterine endometrium can establish a successful dialogue with blastocyst. This study was to investigate the effect of asynchronous embryo transfer on uterine receptivity in mice. Embryos under different stages were transferred into two oviduct sides of a recipient mouse on day 1 of pseudopregnancy. Our results showed the asynchronously transferred embryos can implant in all groups. Compared to zygote-transfer group, the length of implanted embryos is longer in 8-cell embryo- or blastocyst-transfer group. The levels of Snail and COX-2 immunostaining in blastocyst-transfer group are significantly stronger than that in zygote-transfer group. Embryos in blastocyst-transfer group migrate faster than that in zygote-transfer group within uterus. Blastocysts are in a state of developmental delay after they are transferred into oviducts, and they are reactivated and implanted rapidly in uterus. The developmental rate to newborn in zygote-transfer group is obviously higher than that in blastocyst-transfer group, suggesting that a delay in embryo development and implantation will lead to a decrease of litter size. These results indicated that the window of implantation is differentially regulated in two uterine horns of a recipient by embryos at different stages.
Assuntos
Implantação do Embrião/fisiologia , Transferência Embrionária/métodos , Endométrio/fisiologia , Zigoto/transplante , Animais , Blastocisto/citologia , Ciclo-Oxigenase 2/metabolismo , Desenvolvimento Embrionário/fisiologia , Feminino , Masculino , Camundongos , Pseudogravidez/embriologia , Fatores de Transcrição da Família Snail , Fatores de Transcrição/metabolismo , Zigoto/crescimento & desenvolvimentoRESUMO
Polyploid decidual cells are specifically differentiated cells during mouse uterine decidualization. However, little is known about the regulatory mechanism and physiological significance of polyploidization in pregnancy. Here we report a novel role of E2F8 in the polyploidization of decidual cells in mice. E2F8 is highly expressed in decidual cells and regulated by progesterone through HB-EGF/EGFR/ERK/STAT3 signaling pathway. E2F8 transcriptionally suppresses CDK1, thus triggering the polyploidization of decidual cells. E2F8-mediated polyploidization is a response to stresses which are accompanied by decidualization. Interestingly, polyploidization is not detected during human decidualization with the down-regulation of E2F8, indicating differential expression of E2F8 may lead to the difference of decidual cell polyploidization between mice and humans.
Assuntos
Decídua/fisiologia , Proteínas Repressoras/fisiologia , Animais , Proteína Quinase CDC2/metabolismo , Linhagem Celular , Quinases Ciclina-Dependentes/metabolismo , Dano ao DNA , Feminino , Citometria de Fluxo , Hepatócitos/metabolismo , Humanos , Camundongos , Microscopia de Fluorescência , Ovário/metabolismo , Poliploidia , Gravidez , Prenhez , Progesterona/metabolismo , Transdução de Sinais , Superóxido Dismutase/metabolismo , Útero/metabolismoRESUMO
Secretin, a classical gastrointestinal and neuroendocrine peptide, plays an important role in maintaining the body fluid balance. However, the expression and regulation of secretin in the reproductive system are still unknown. In our study, secretin is specifically expressed in the decidua on days 5 to 8 of pregnancy. Secretin expression is not detected under delayed implantation but is stimulated after estrogen activation and under artificial decidualization. Progesterone induces secretin expression in ovariectomized mice and cultured stromal cells, which is abrogated by specific LY294002. Because secretin is mainly localized in the decidua and also strongly expressed during in vitro decidualization, secretin may play a role during mouse decidualization through regulating cyclic adenosine monophosphate level.
Assuntos
Implantação do Embrião/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Progesterona/farmacologia , Secretina/biossíntese , Útero/metabolismo , Animais , Células Cultivadas , Implantação do Embrião/efeitos dos fármacos , Feminino , Camundongos , Gravidez , Progesterona/fisiologia , Útero/efeitos dos fármacosRESUMO
L-Arginine (L-Arg), a conditional essential amino acid in adults, has been shown to enhance pregnancy outcome. Argininosuccinate synthase (Ass1) and argininosuccinate lyase (Asl) are the key enzyme for L-Arginine (L-Arg) biosynthesis. Based our microarray analysis, Ass1 expression is upregulated significantly at implantation site on day 5 of pregnancy compared to that at inter-implantation site. However, the expression, regulation and function of Ass1 during early pregnancy remain unknown. Here we found that Ass1 is highly expressed in mouse decidua and uterine stromal cells undergoing decidualization, and Asl is weakly expressed in mouse decidua and uterine stromal cells undergoing decidualization. α-Methyl-DL-aspartic acid (MDLA), a specific inhibitor for Ass1, can significantly increase the rate of embryonic reabsorption. Under in vitro induced decidualization, MDLA clearly inhibits the expression of decidual/trophoblast prolactin-related protein (Dtprp), a marker for decidualization in mice. Only Ass1 expression is induced by cAMP through PKA/p-Creb signaling pathway. Results from our cell culture models further indicates that the high level of L-Arg enhances stromal proliferation, while enzymatic activity or Ass1 expression level is essential to determine the magnitude of both mouse and human decidualization. Interestingly, L-Arg at high concentration down-regulates Ass1 and Asl expression by negative feedback to maintain L-Arg homeostasis. These findings highlight that cAMP-induced Ass1 expression is important in controlling the magnitude of decidualization through regulating L-Arg level.
Assuntos
Argininossuccinato Sintase/genética , AMP Cíclico/fisiologia , Decídua/enzimologia , Animais , Arginina/fisiologia , Argininossuccinato Liase/genética , Argininossuccinato Liase/metabolismo , Argininossuccinato Sintase/metabolismo , Linhagem Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Decídua/fisiologia , Implantação do Embrião , Indução Enzimática , Feminino , Humanos , Masculino , Camundongos , GravidezRESUMO
Although decidualization is crucial for the establishment of successful pregnancy, the molecular mechanism underlying decidualization remains poorly understood. Crystallin αB (CryAB), a small heat shock protein (sHSP), is up-regulated and phosphorylated in mouse decidua. In mouse primary endometrial stromal cells, CryAB is induced upon progesterone treatment via HIF1α. In addition, CryAB is strongly phosphorylated through the p38-MAPK pathway under stress or during in vitro decidualization. Knockdown of CryAB results in the increase of apoptosis of stromal cells and inhibits decidualization under oxidative or inflammatory stress. Our data indicate that CryAB protects decidualization against stress conditions.
Assuntos
Decídua/citologia , Cadeia B de alfa-Cristalina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Hipóxia Celular , Decídua/efeitos dos fármacos , Decídua/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Gravidez , Progesterona/farmacologia , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Cadeia B de alfa-Cristalina/genéticaRESUMO
OBJECTIVE: To determine Claudin-3 expression and its regulatory factors during embryo implantation. DESIGN: Experimental mouse models and cell culture. SETTING: University research laboratory. ANIMAL(S): Sexually mature female CD-1 strain mice. INTERVENTION(S): Ovariectomy and treatments. MAIN OUTCOME MEASURE(S): In situ hybridization and immunohistochemistry for detecting Claudin-3 messenger RNA and protein expression in mouse uterus, respectively; Western blot for detecting protein levels; immunofluorescence for detecting Claudin-3 protein in cultured cells. RESULT(S): Claudin-3 is strongly expressed in the uterine luminal epithelium on days 3 and 4 of pregnancy, and diminished at day 5 implantation sites. Then it is expressed at secondary decidual zone on day 8. Pseudopregnant uteri have a similar expression pattern as pregnant uteri from days 1-5. Claudin-3 expression is down-regulated after delayed implantation is activated by estrogen (E) treatment. Meanwhile Claudin-3 expression is stimulated by artificial decidualization. In ovariectomized mice, P induces Claudin-3 expression in the luminal epithelium, which is abrogated by P receptor antagonist RU486. Heparin-binding-epidermal growth factor (HB-EGF) down-regulates Claudin-3 expression, but enhances transcription factor Snail expression. In human endometrial epithelial ECC-1 cells, both E and P could stimulate Claudin-3 expression, whereas HB-EGF decreases Claudin-3 and increases Snail expression. CONCLUSION(S): Claudin-3 expression in uterine luminal epithelium is stimulated by P and suppressed by HB-EGF in mice and humans.
Assuntos
Claudina-3/metabolismo , Células Epiteliais/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Progesterona/metabolismo , Junções Íntimas/metabolismo , Útero/metabolismo , Animais , Células Cultivadas , Claudina-3/genética , Implantação Tardia do Embrião , Células Epiteliais/efeitos dos fármacos , Estrogênios/metabolismo , Feminino , Regulação da Expressão Gênica , Fator de Crescimento Semelhante a EGF de Ligação à Heparina , Antagonistas de Hormônios/farmacologia , Camundongos , Ovariectomia , Gravidez , Receptores de Progesterona/antagonistas & inibidores , Receptores de Progesterona/metabolismo , Fatores de Transcrição da Família Snail , Junções Íntimas/efeitos dos fármacos , Fatores de Tempo , Fatores de Transcrição/metabolismo , Útero/efeitos dos fármacosRESUMO
The epithelial-mesenchymal transition plays a critical role in embryonic development, cancer progression, and metastasis. Decidualization is the process by which the fibroblast-like endometrial stromal cells differentiate into polygonal epithelial-like cells. However, it is still unclear whether mesenchymal-epithelial transition (MET) occurs during decidualization. The aim of this study was to examine whether decidualization causes the downregulation of some mesenchymal markers and upregulation of some epithelial markers in cultured uterine stromal cells. We showed that decidualization causes the downregulation of snail and vimentin expression, and upregulation of E-cadherin and cytokeratin expression. During in vitro decidualization, cultured stromal cells lose elongated shape and show epithelium-like characteristics. Our data suggest that the process of MET may exist during decidualization.
Assuntos
Decídua/citologia , Decídua/fisiologia , Transição Epitelial-Mesenquimal/fisiologia , Animais , Células Cultivadas , Feminino , Humanos , Camundongos , GravidezRESUMO
Embryo implantation requires a precise synchronism between the receptive uterus and activated blastocyst and is regulated by complicated molecular networks. Although many implantation-related genes have been identified, the crosstalk among them is still unknown. Snail, a transcription repressor, plays a central role during epithelial-mesenchymal transition. Our previous study showed that Snail is highly expressed at implantation site in mouse uterus. This study was to examine how Snail is related with other implantation-related genes in mice. Uterine stromal cells were isolated from mouse uteri on day 4 of pregnancy and treated with HB-EGF. Snail was induced significantly by HB-EGF. By using specific inhibitors and siRNA, we demonstrated that HB-EGF induction on Snail expression is dependent on the EGFR-ERK-Stat3 pathway. Cox-2 was regulated by Snail. The current findings demonstrate that Snail can relate with HB-EGF, Stat3 and Cox-2 and may play a role during mouse embryo implantation and decidualization.
Assuntos
Decídua/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Fatores de Transcrição/genética , Ativação Transcricional , Animais , Células Cultivadas , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Implantação do Embrião , Receptores ErbB/metabolismo , Feminino , Fator de Crescimento Semelhante a EGF de Ligação à Heparina , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Fosforilação , Gravidez , Processamento de Proteína Pós-Traducional , Fator de Transcrição STAT3/metabolismo , Fatores de Transcrição da Família Snail , Fatores de Transcrição/metabolismoRESUMO
Interleukin 1 (IL-1) is one of the most potent proinflammatory cytokines possessing a wide spectrum of inflammatory, metabolic, hemopoietic, and immunologic properties. In addition, the IL-1 system has been considered relevant in regulating communication between the blastocyst and the endometrium. Interleukin 1 receptor type II (IL1R2) acts as a negative regulator for IL-1 actions and has been termed a "decoy receptor." The aim of this study was to determine the expression pattern of IL1R2 gene in mouse uterus during the early pregnancy. Both in situ hybridization and immunohistochemistry were performed to examine the spatial localization of IL1R2 expression in mouse uteri. Real-time quantitative polymerase chain reaction analyses were used to quantify Il1r2 messenger RNA (mRNA) level under in vivo and in vitro artificial decidualization. By transfecting Il1r2 gene in cultured stromal cells from day 4 pregnant mice, we detected the expression of Dtprp, a well-known marker for decidualization. Our results showed that IL1R2 gene expression was mainly localized in decidual cells close to the implanting embryo during days 5 to 8 of pregnancy. Under in vivo and in vitro artificial decidualization, Il1r2 was significantly upregulated. Dtprp mRNA expression was also upregulated by Il1r2 overexpression. Our data suggest that IL1R2 may play an important role during mouse decidualization.
Assuntos
Decídua/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Receptores Tipo II de Interleucina-1/biossíntese , Animais , Feminino , Camundongos , Gravidez , RNA Mensageiro/biossínteseRESUMO
BACKGROUND: Junctional adhesion molecule 2 (Jam2) is a member of the JAM superfamily. JAMs are localized at intercellular contacts and participated in the assembly and maintenance of junctions, and control of cell permeability. Because Jam2 is highly expressed in the luminal epithelium on day 4 of pregnancy, this study was to determine whether Jam2 plays a role in uterine receptivity and blastocyst attachment in mouse uterus. METHODOLOGY/PRINCIPAL FINDINGS: Jam2 is highly expressed in the uterine luminal epithelium on days 3 and 4 of pregnancy. Progesterone induces Jam2 expression in ovariectomized mice, which is blocked by progesterone antagonist RU486. Jam2 expression on day 4 of pregnancy is also inhibited by RU486 treatment. Leukemia inhibitory factor (LIF) up-regulates Jam2 protein in isolated luminal epithelium from day 4 uterus, which is blocked by S3I-201, a cell-permeable inhibitor for Stat3 phosphorylation. Under adhesion assay, recombinant Jam2 protein increases the rate of blastocyst adhesion. Both soluble recombinant Jam2 and Jam3 can reverse this process. CONCLUSION: Jam2 is highly expressed in the luminal epithelium of receptive uterus and up-regulated by progesterone and LIF via tyrosine phosphorylation of Stat3. Jam2 may play a role in the interaction between hatched blastocyst and receptive uterus.