Expression of Betacellulin and Epiregulin Genes in the Mouse Uterus Temporally by the Blastocyst Solely at the Site of Its Apposition Is Coincident with the “Window” of Implantation

Das, Sanjoy K.; Das, Niranjan; Wang, J.; Lim, Hyunjung Jade; Schryver, Brian; Plowman, Gregory D.; Dey, Sudhansu K.

doi:10.1006/dbio.1997.8694

Cited by 118 publications

(69 citation statements)

References 35 publications

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“…There are previous reports that genes, which encode the EGF-like growth factors, cytokines and other inflammatory mediators, extracellular matrix proteins, cell cycle molecules, and immunoregulatory proteins, are expressed at the site of estrogen-induced implantation in a pattern similar to their expression in natural implantation (17,27,30,(31)(32)(33)(34)(35)(36)(37)(38). In this respect, our microarray results are consistent with the previously described expression of several steroid hormone-sensitive and implantationspecific genes, including the genes encoding Cyp1b1, connexin …”

Section: Discussionmentioning

confidence: 99%

Global Gene Expression Analysis to Identify Molecular Markers of Uterine Receptivity and Embryo Implantation

Reese¹,

Das²,

Paria³

et al. 2001

Journal of Biological Chemistry

204

152

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Infertility and spontaneous pregnancy losses are an enduring problem to women's health. The establishment of pregnancy depends on successful implantation, where a complex series of interactions occurs between the heterogeneous cell types of the uterus and blastocyst. Although a number of genes are implicated in embryo-uterine interactions during implantation, genetic evidence suggests that only a small number of them are critical to this process. To obtain a global view and identify novel pathways of implantation, we used a dual screening strategy to analyze the expression of nearly 10,000 mouse genes by microarray analysis. Comparison of implantation and interimplantation sites by a conservative statistical approach revealed 36 up-regulated genes and 27 down-regulated genes at the implantation site. We also compared the uterine gene expression profile of progesterone-treated, delayed implanting mice to that of mice in which delayed implantation was terminated by estrogen. The results show up-regulation of 128 genes and down-regulation of 101 genes after termination of the delayed implantation. A combined analysis of these experiments showed specific up-regulation of 27 genes both at the implantation site and during uterine activation, representing a broad diversity of molecular functions. In contrast, the majority of genes that were decreased in the combined analysis were related to host immunity or the immune response, suggesting the importance of these genes in regulating the uterine environment for the implanting blastocyst. Collectively, we identified genes with recognized roles in implantation, genes with potential roles in this process, and genes whose functions have yet to be defined in this event. The identification of unique genetic markers for the onset of implantation signifies that genome-wide analysis coupled with functional assays is a promising approach to resolve the molecular pathways required for successful implantation.

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Section: Discussionmentioning

confidence: 99%

Global Gene Expression Analysis to Identify Molecular Markers of Uterine Receptivity and Embryo Implantation

Reese¹,

Das²,

Paria³

et al. 2001

Journal of Biological Chemistry

204

152

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“…A 1.8-kilobase pair cDNA fragment (EcoRI/SacI) of a mouse cDNA clone for c-fos (41) was subcloned in pSP64 vector at EcoRI/SacI sites. The clone description for ribosomal protein L-7 (rpL7) cDNA was reported earlier (42).…”

Section: Methodsmentioning

confidence: 99%

“…Northern blots were prehybridized, hybridized, and washed as described by us (40,42). Quantitation of hybridized bands was analyzed by densitometric scanning.…”

Section: Methodsmentioning

confidence: 99%

Estrogen Targets Genes Involved in Protein Processing, Calcium Homeostasis, and Wnt Signaling in the Mouse Uterus Independent of Estrogen Receptor-α and -β

Das¹,

Tan²,

Raja³

et al. 2000

Journal of Biological Chemistry

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Estrogen actions in target organs are normally mediated via activation of nuclear estrogen receptors (ERs). By using mRNA differential display technique, we show, herein, that estradiol-17␤ (E 2 ) and its catechol metabolite 4-hydroxy-E 2 (4OHE 2 ) can modulate uterine gene expression in ER␣(؊/؊) mice. Whereas administration of E 2 or 4OHE 2 rapidly up-regulated (4 -8-fold) the expression of immunoglobulin heavy chain binding protein (Bip), calpactin I (CalP), calmodulin (CalM), and Sik similar protein (Sik-SP) genes in ovariectomized wildtype or ER␣(؊/؊) mice, the expression of secreted frizzled related protein-2 (SFRP-2) gene was down-regulated (4-fold). Bip, CalP, and CalM are calcium-binding proteins and implicated in calcium homeostasis, whereas SFRP-2 is a negative regulator of Wnt signaling. Bip and Sik-SP also possess chaperone-like functions. Administration of ICI-182,780 or cycloheximide failed to influence these estrogenic responses, demonstrating that these effects occur independent of ER␣, ER␤, or protein synthesis. In situ hybridization showed differential cell-specific expression of these genes in wild-type and ER␣(؊/؊) uteri. Although progesterone can antagonize or synergize estrogen actions, it had minimal effects on these estrogenic responses. Collectively, the results demonstrate that estrogens have a unique ability to influence specific genes in the uterus not involving classical nuclear ERs.Estrogens regulate diverse physiological responses including normal functioning of the reproductive and cardiovascular systems and bone metabolism (1-3). The uterus is a primary target for various estrogenic responses during the cycle and pregnancy. In the mouse, estrogen induces uterine epithelial cell proliferation, and together with progesterone (P 4 ) 1 it directs stromal cell proliferation and epithelial cell differentiation. These coordinated estrogen and P 4 interactions prepare the uterus to the receptive state for implantation (reviewed in Ref. 4). The mechanism by which estrogen renders the P 4 -primed uterus receptive for implantation is not clearly understood.Estrogen actions are primarily executed by its binding to nuclear estrogen receptors, ER␣ and/or ER␤, which are ligandinducible transcription factors (5, 6). They modulate transcription of genes by virtue of their binding as hormone receptor complexes to specific DNA sequences (hormone response elements) in target promoters (5, 6). Despite the classical estrogenic actions, there is increasing evidence that gene transactivation or modulation of cell functions by estrogens is also mediated independent of nuclear ERs (7-10). In many cells, a myriad of estrogenic effects occurs rapidly within seconds or minutes. These responses do not require RNA or protein synthesis and are considered to be mediated by estrogen binding to the plasma membrane (10 -12). For example, increases in intracellular cAMP, calcium influx, inositol triphosphate, and release of prolactin are all attributed to membrane-mediated estrogen actions (10 -12). Although the pre...

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“…For instance, blastocysts can only implant once they have been activated by uterine factor(s) that are regulated by ovarian steroid hormones (2). Conversely, expression of several uterine genes are regulated by a signal(s) emanating from activated blastocysts (3,4). Multiple signaling pathways have been shown to participate in the implantation process, and several cytokines and growth factors have been shown to be expressed in the uterus at the time of implantation and to play important roles in this process (5).…”

mentioning

confidence: 99%

Uterine Wnt/β-catenin signaling is required for implantation

Mohamed

Jonnaert

Labelle‐Dumais

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

204

161

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Successful implantation relies on precisely orchestrated and reciprocal signaling between the implanting blastocyst and the receptive uterus. We have examined the role of the Wnt͞␤-catenin signaling pathway during the process of implantation and demonstrate that this pathway is activated during two distinct stages. Wnt͞␤-catenin signaling is first transiently activated in circular smooth muscle forming a banding pattern of activity within the uterus on early day 4. Subsequently, activation is restricted to the luminal epithelium at the prospective site of implantation. Activation at both sites requires the presence of the blastocyst. Furthermore, inhibition of Wnt͞␤-catenin signaling interferes with the process of implantation. Our results demonstrate that the Wnt͞␤-catenin signaling pathway plays a central role in coordinating uterus-embryo interactions required for implantation.blastocyst ͉ uterus A crucial event during mammalian embryonic development is the process of implantation, during which the free-living blastocyst attaches to the uterine endometrium. Successful implantation depends on precisely orchestrated and reciprocal signaling between the implanting blastocyst and the receptive uterus (1). For instance, blastocysts can only implant once they have been activated by uterine factor(s) that are regulated by ovarian steroid hormones (2). Conversely, expression of several uterine genes are regulated by a signal(s) emanating from activated blastocysts (3, 4). Multiple signaling pathways have been shown to participate in the implantation process, and several cytokines and growth factors have been shown to be expressed in the uterus at the time of implantation and to play important roles in this process (5). However, there is increasing evidence that members of other families of growth factors implicated in embryogenesis may also participate in the implantation process. It has been demonstrated that members of the hedgehog, bone morphogenetic, and Wnt proteins are expressed in the uterus at the time of implantation (6). However, the precise role of these different growth factor signaling pathways in the implantation process has not been determined. Furthermore, the cell types within the uterus that respond to these growth factors are not known. In this study, we set out to determine the role of the canonical Wnt͞␤-catenin signaling pathway in the implantation process. We demonstrate that this pathway is activated during two distinct stages before implantation. Signaling is transiently detected in circular smooth muscle forming a banding pattern of activity. Subsequently, activation is restricted to the luminal epithelium at the prospective site of implantation. Activation at both sites requires the presence of the blastocyst. Furthermore, we show that inhibition of Wnt͞␤-catenin signaling interferes with the process of implantation. Materials and MethodsMating and Experimental Manipulation of Transgenic Animals. The generation and characterization of the TCF͞Lef-LacZ transgenic mice have been described in ...

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Expression of Betacellulin and Epiregulin Genes in the Mouse Uterus Temporally by the Blastocyst Solely at the Site of Its Apposition Is Coincident with the “Window” of Implantation

Cited by 118 publications

References 35 publications

Global Gene Expression Analysis to Identify Molecular Markers of Uterine Receptivity and Embryo Implantation

Global Gene Expression Analysis to Identify Molecular Markers of Uterine Receptivity and Embryo Implantation

Estrogen Targets Genes Involved in Protein Processing, Calcium Homeostasis, and Wnt Signaling in the Mouse Uterus Independent of Estrogen Receptor-α and -β

Uterine Wnt/β-catenin signaling is required for implantation

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