{"paper_id":"18c0b5d6-9121-4dd3-a10f-c0ee12a63019","body_text":"BioMed Central\nPage 1 of 6\n(page number not for citation purposes)\nReproductive Biology and \nEndocrinology\nOpen AccessReview\nUterine receptivity and implantation: The regulation and action of \ninsulin-like growth factor binding protein-1 (IGFBP-1), HOXA10 \nand forkhead transcription factor-1 (FOXO-1) in the baboon \nendometrium\nJJK i m *1 and Asgerally T Fazleabas2\nAddress: 1Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL, USA and 2Department of Obstetrics and Gynecology, \nUniversity of Illinois at Chicago, Chicago, IL, USA\nE m a i l :  JJK i m *-j - k i m 4 @ n o r t h w e s t e r n . edu; Asgerally T Fazleabas - asgi@uic.edu\n* Corresponding author    \nAbstract\nIn primates, the phase of the menstrual cycle wh en the uterus becomes receptive is initially\ndependent on estrogen and progesterone. Furt her morphological and biochemical changes are\ninduced as a result of biochemical signals be tween the embryo and the maternal endometrium.\nBlastocyst implantation in the baboon usually occurs between 8 and 10 days post ovulation and is\nsimilar to that described for the rhesus macaque . In the baboon, when chorionic gonadotropin is\ninfused in a manner that mimics blastocyst transit, this has physiological effects on the three major\ncell types in the uterine endometrium. The lu minal epithelium undergo es endoreplication and\ndistinct epithelial plaques are evident. The glandular epithelium responds by inducing transcriptional\nand post-translational modifica tions in the major secretory pr oduct, glycodelin. The stromal\nfibroblasts initiate their differentiation process into a decidual phenotype and are characterized by\nthe expression of actin filaments.  Decidualization, is the major ch ange that occurs in the primate\nendometrium after conception. During this pr ocess the fibroblast-like stromal cells change\nmorphologically into polygonal cells and express sp ecific decidual proteins. Studies in the baboon\ndemonstrated that insulin-like growth factor binding protein-1 (I GFBP-1) gene expression is a\nconceptus-mediated response. Subsequent studies in vitro established that IGFBP-1 is\ntranscriptionally regulated by FOXO1 and HO XA10 which together upregulate the IGFBP-1\npromoter activity. A baboon en dometriosis model was utilized to determine if the changes\nobserved during uterine receptivity in normal ly cycling animals were compromised. The data\nsuggests that in animals with disease, markers of uterine re ceptivity are not appropriately\nexpressed in the eutopic endometrium. It is possible that these differences influence the fertility of\nthe animals with disease and the baboon could be used as a primate model to study the causes of\ninfertility as a result of endometriosis.\nBackground\nThe dialogue that occurs between the preimplantation\nembryo and the uterus is one of true elegance. Although\nthe precise molecules and events involved remain unclear,\nit is well known that the initiation of pregnancy requires a\nprecisely timed synchrony between endometrial develop-\nPublished: 16 June 2004\nReproductive Biology and Endocrinology 2004, 2:34 doi:10.1186/1477-7827-2-34\nReceived: 01 March 2004\nAccepted: 16 June 2004\nThis article is available from: http://www.rbej.com/content/2/1/34\n© 2004 Kim and Fazleabas; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in \nall media for any purpose, provided this notice is preserved along with the article's original URL. \n\nReproductive Biology and Endocrinology 2004, 2 http://www.rbej.com/content/2/1/34\nPage 2 of 6\n(page number not for citation purposes)\nment and the implanting blastocyst. In primates, at the\nappropriate phase of the menstrual cycle, the uterus\nbecomes \"receptive\" and enables the blastocyst to attach.\nThis \"receptive window\" is initially dependent on estro-\ngen and progesterone. Further morphological and bio-\nchemical changes are induced within the uterus by signals\nfrom the developing embryo and following trophoblast\ninvasion.\nUterine receptivity and implantation in the baboon can\nbe categorized into three distinct phases. Phase I is regu-\nlated by estrogen and progesterone and is evident between\ndays 8 and 10 post-ovulation (PO) of the normal men-\nstrual cycle. Morphologically it is characterized by the\npresence of columnar epithelium with microvilli and an\nincrease in stromal cells proliferation [1]. At the biochem-\nical level, there is a loss of estrogen receptor (ER α) and\nprogesterone receptor (PR) in the luminal epithelium [2]\ntogether with a marked reduction of the polymorphic\nmucin, Muc-1 expression [3]. Coincident with the\ndecrease in Muc-1 staining, there is an increase in smooth\nmuscle myosin II (SMM II) expression in the luminal and\nglandular epithelium [4] and the appearance of pinopod-\nlike structures on the surface epithelium, similar to those\nreported in the human [5]. The second phase of uterine\nreceptivity is induced by blastocyst 'signals' superimposed\non the estrogen/progesterone-primed receptive\nendometrium. This phase is associated with functional\nand morphological changes in the endometrium that are\ndistinct from those observed at a comparable time of a\nnonpregnant cycle (i.e. phase I of uterine receptivity).\nPhase III of uterine receptivity is initiated following blast-\nocyst attachment and implantation. A universal response\nis the significant increase in the permeability of the subep-\nithelial capillaries surrounding the blastocyst [6,7]. In pri-\nmates the morphological changes associated with\nimplantation have been extensively studied and elegantly\nreviewed by Enders [8]. In general, together with glandu-\nlar hypertrophy, stromal cell decidualization is initiated\nand is accompanied by increased extracellular matrix\n(ECM) accumulation.\nIn this review, a brief summary of the studies in the\nbaboon that demonstrate the modulation of the uterus by\nembryonic signals (Phase II) is given. The molecular regu-\nlation of stromal cell differentiation (Phase III) will be the\nfocus of this review and the aberration of uterine receptiv-\nity in baboons with endometriosis will be discussed.\nInfluence of embryonic signals on uterine receptivity – \nphase II\nSeveral lines of evidence demonstrate that embryo-\nderived factors directly or indirectly influence endome-\ntrial receptivity and implantation in primates. Studies in\nthe rhesus monkey indicate that endometrial physiology\nduring the midluteal phase in the presence of the concep-\ntus is discernibly different from that in the nonfecund\nmidluteal phase [9]. An early maternal response to preg-\nnancy in the luminal epithelium of primates is the forma-\ntion of the epithelial plaque [10]. This response is\ncharacterized by hypertrophy of the surface epithelium\nand cells in the neck glands that round up and form acinar\nclusters [11,12]. In the baboon, chorionic gonadotropin\n(CG), when infused in a manner that mimics blastocyst\ntransit, has physiological effects on the three major cell\ntypes in the uterine endometrium (i.e. luminal and glan-\ndular epithelium and stromal fibroblasts [13]). The effects\nof CG on glandular transformation and stromal cell differ-\nentiation are direct, and occur independent of the ovary\n[13]. The glandular response to CG infusion is character-\nized by a marked increase in transcriptional and post-\ntranslational modulation of glycodelin [13]. Synthesis of\nglycodelin by the glandular epithelium parallels the rise\nand later decline of CG in the peripheral circulation [14].\nThe primary effect of CG on stromal fibroblasts is the\ninduction of α-smooth muscle actin ( αSMA; 13, 15). It\nhas been hypothesized that the induction of αSMA in\nstromal fibroblasts occurs as a consequence of the binding\nof integrins on the stromal cell membranes (that are also\ninduced in response to CG) to secreted ECM proteins\n[16]. The interaction between integrins and the ECM\ninduces changes in the actin cytoskeleton that are thought\nto be critical for signal transduction [17,18].\nDecidualization – phase III\nOne of the fundamental requirements for the successful\nestablishment and maintenance of pregnancy in the pri-\nmate is the decidualization of the endometrium. Decidu-\nalization is defined as the differentiation of the fibroblast-\nlike mesenchymal cells in the endometrium to a decidual\ncell which is morphologically and biochemically distinct\n[19]. The decidualized cell biochemically expresses new\nproteins such as prolactin and insulin-like growth factor\nbinding protein-1 (IGFBP-1; 1).\nIn the human, regardless of whether implantation occurs,\nstromal edema is observed on day 23 of the menstrual\ncycle and is followed 3 to 4 days later by a predecidual\nreaction which begins around the spiral arteries and\nspreads through the upper two-thirds of the endometrium\n[20]. If implantation occurs, the reaction is intensified\nand becomes the decidua of pregnancy. In contrast, the\nbaboon does not undergo a predecidual reaction during\nthe menstrual cycle [12,21]. However, following implan-\ntation, the stromal fibroblasts undergo extensive modifi-\ncation to form the decidua in the baboon (11,12, 22).\nTurner [23] and Bryce and Teacher [24] first suggested that\ndecidualization is regulated by the trophoblast. In vivo\ndata clearly demonstrate that decidualization in the\nbaboon, based on IGF-I receptor, IGFBP-1 and prolactin\n\nReproductive Biology and Endocrinology 2004, 2 http://www.rbej.com/content/2/1/34\nPage 3 of 6\n(page number not for citation purposes)\nexpression, is a conceptus-induced phenomenon, first evi-\ndent at the implantation site between days 18 and 25 of\npregnancy [25,26]. Treatment of endometrial stromal\ncells in cell culture with estrogen and progesterone, which\ncan decidualize human stromal cells, is insufficient to\nfully decidualize stromal cells isolated from the baboon\nendometrium. An additional factor, i.e. dibutyryladenos-\nine 3':5' cyclic monophosphate (dbcAMP) is required,\nsuggesting that a conceptus-mediated factor involving\ncAMP-mediated pathways is important in the baboon\n[27].\nAlthough there are many studies that have defined the\nmorphological and biochemical end points of a decidual\ncell [12,28], the sequence of cellular and molecular events\nassociated with the transformation of a stromal fibroblast\nto a secretory decidual cell has yet to be elucidated. IGFBP-\n1 is not only a marker for decidualization but also a para-\ncrine/autocrine factor which is intimately involved in the\nsequence of events leading from implantation to normal\nfetal outcome. By studying the factors which regulate\nIGFBP-1 gene expression, a general sense of the types of\nchanges that occur during the process of decidualization\ncan be obtained.\nIGFBP-1 gene regulation\nMany studies have demonstrated the regulation of the\nIGFBP-1 gene in both the liver and the endometrium.\nMultiple factors contribute to the regulation of IGFBP-1\ngene expression, including insulin, glucocorticoids, pro-\ngesterone, cytokines and hypoxia [29-32]. In the decidual-\nized human endometrium, progesterone induces IGFBP-1\nsynthesis perhaps via a glucocorticoid response element\n[33]. Further modulation of its expression in vitro is medi-\nated by cAMP [34]. Many of the important cis-regulatory\nelements are located within 500 bp of the transcription\nstart site. [35]. The hepatocyte nuclear factor 1 (HNF1)\nbinding region, insulin response element (IRE), gluoco-\ncorticoid response element (GRE) and TATA element are\nhighly conserved among the human, rat and mouse\nIGFBP-1 promoters, suggesting a crucial, evolutionarily\nconserved role for these gene promoter regions in its reg-\nulation. In the recent years, there has been great interest in\nthe regulation of IGFBP-1 by FOXO1, a member of the\nFOXO sub-family of forkhead/winged-helix family of\ntranscription factors in liver-derived cells [36-39]. The\nDNA-binding domain of FOXO1 is comprised of three\ntightly packed alpha helical domains and a C-terminal\nbasic region [40]. It is the third helix (H3) that establishes\nDNA base contacts within the major groove of its recogni-\ntion sequence. The IGFBP-1 promoter contains an FOXO1\nbinding site (GCAAAACAA) in the IRE of the human\nIGFBP-1 promoter.\nFOXO1 is expressed in the baboon endometrium and is\nupregulated during the luteal phase of the menstrual cycle\nwhich intensifies during pregnancy [35]. Furthermore,\nFOXO1 can upregulate the IGFBP-1 promoter in endome-\ntrial stromal cells [35]. Studies have shown FOXO1 to\nphysically associate with additional nuclear transcription\nfactors and cause repression or transactivation of genes.\nFOXO1 can interact with the estrogen receptor, retinoic\nacid receptor, and thyroid hormone receptor causing\neither repressive or activating effects on nuclear receptor\nmediated genes [41,42]. FOXO1 can also associate with\nand function cooperatively with CCAAT/enhancer-bind-\ning protein (C/EBP) beta to cause a significant upregula-\ntion of the decidual prolactin promoter in response to\ncAMP agonists [43]. FOXO1 can physically associate with\nHOXA10, another nuclear transcription factor which then\nacts cooperatively to increase the IGFBP-1 promoter activ-\nity [35].\nHOXA10 is one member of the homeobox (HOX) gene\nfamily. Homeobox genes are involved in the genetic con-\ntrol of development, in particular in the specification of\nthe body plan, pattern formation, the determination of\ncell fate, and several other basic developmental processes\n(reviewed in 44). Proteins in the homeobox gene family\ncontain a unique homeodomain that is a 61 amino acid\nresidue polypeptide which represents the DNA-binding\ndomain of the proteins.\nHOX proteins can regulate genes in adult tissues. Hoxa5\n[45] and HOXA10 [46] stimulate the p53 promoter in\nbreast cancer cells and promote the expression of the pro-\ngesterone receptor [47]. Other targets of HOXA10 regula-\ntion include beta 3 integrin [48] and empty spiracles\nhomolog 2(EMX2) [49]. In the developing reproductive\ntract, four genes of the HOXA cluster (HOXA9, HOXA10,\nHOXA11, and HOXA13) are expressed [50]. HOXA10 is\nexpressed in the developing uterus, specifically in the\nendometrial glands and stroma of the endometrium\nwhere its expression is dependent on the stage of the men-\nstrual cycle, dramatically increasing at the time of implan-\ntation [50-52]. HOXA10 deficient mice exhibit uterine\nfactor infertility due to implantation defects. Specifically,\ndecidualization of the endometrium is severely compro-\nmised during blastocyst implantation [53]. The role of\nHOX genes on IGFBP-1 regulation has been demonstrated\nfor the first time using transgenic mice over-expressing\nHOXA5. These mice exhibit a 12-fold increase of IGFBP-1\nexpression in the liver and undergo growth arrest during\nweeks two and three of postnatal development, resulting\nin proportionate dwarfism [54]. HOXA10 has a modest\neffect on IGFBP-1 promoter activity, but when FOXO1 is\npresent, promoter activity is upregulated in a cooperative\nmanner [35]. For this to occur, binding of FOXO1 to the\nIRE is required.\n\nReproductive Biology and Endocrinology 2004, 2 http://www.rbej.com/content/2/1/34\nPage 4 of 6\n(page number not for citation purposes)\nStudies have suggested that HOX family members interact\nwith cofactors such as PBX, the mammalian homolog of\nDrosophila extradenticle [55-57]. It is believed that interac-\ntions with PBX cofactors may contribute to the regulatory\ncontrol and refinement of HOX protein function. Given\nthat there is a high proportion of presumptive HOX bind-\ning sites on any given promoter and the affinity of HOX\nproteins for nonspecific sites is relatively strong, it is not\nunreasonable to assume a need for cofactors for site-spe-\ncific recognition. It is possible that there are multiple\npotential HOXA10 binding sites on the IGFBP-1 pro-\nmoter. Whether these binding sites are functional may\ndepend on the availability of FOXO1 to interact with\nHOXA10 and assist in its recruitment to the IGFBP-1 pro-\nmoter. It is possible that HOXA10 stabilizes FOXO1 DNA\nbinding and in turn modulates specificity of HOX DNA\nbinding.\nThe cooperative action of FOXO1 and HOXA10 is highly\nintriguing with great potential implications. Not only are\nFOXO1 and HOX transcription factors expressed in\nnumerous tissues and cell types, these two transcription\nfactors have independently been shown to be critical reg-\nulators of genes. The possibility that FOXO1 and HOX\nproteins, by associating with one another can regulate\ngenes more powerfully and specifically than by them-\nselves, is extremely provocative.\nThe repertoire of gene expression during conceptus-\ninduced decidualization is very different from a non-preg-\nnant endometrium. When critical genes are aberrantly\nexpressed during the decidualization process or even dur-\ning the window of implantation, this could result in the\nfailure of the blastocyst to implant or inadequate implan-\ntation. Studies have demonstrated that the eutopic\nendometrium of women with endometriosis expresses an\naberrant pattern of genes and several markers of uterine\nreceptivity are abnormally or not expressed [58].\nUterine receptivity in endometriosis\nWomen and baboons with endometriosis have a lowered\nfecundity [59,60]. Endometriosis, which is characterized\nby the presence of a functional endometrium outside of\nthe uterine cavity, is a condition that affects five million\nAmerican women. The etiology of endometriosis is\nunclear; however, the most widely accepted hypothesis for\nits development is retrograde menstruation, where frag-\nments of menstrual endometrium are refluxed through\nthe fallopian tubes into the peritoneal cavity [61]. The\nbaboon has been used as a model to understand this dis-\nease. Intraperitoneal autotransplantation of menstrual\nendometrium in the baboon results in experimental\nendometriosis, supporting Sampson's theory of retro-\ngrade menstruation. This method of induction resulted in\nred raised and reddish-blue implants to scared lesions\nwith powder-black appearance that were macroscopically\nsimilar to those seen in women with spontaneous\nendometriosis [62]. There is also evidence that the\nbaboon can spontaneously develop endometriosis: how-\never, it is unclear whether this is truly a spontaneous con-\ndition or whether it is induced by repetitive surgical\nmanipulation [63].\nGlycodelin, αSMA, and αvβ3, which have been previously\ncharacterized as markers of uterine receptivity, are absent\nfrom eutopic endometrium during the window of\nimplantation in baboons and humans with endometrio-\nsis [59,64]. The lack of induction of glycodelin and αSMA\nis seen at early stages of endometriosis in the baboon. An\nunderstanding of the mechanisms by which the expres-\nsion of these genes is controlled may elucidate the reasons\nfor implantation failure in women with endometriosis.\nIn recent years, studies have shown that the gene expres-\nsion profile in the endometrium of women with endome-\ntriosis is aberrant [58,65-68]. HOXA10 downregulated in\nthe endometrium of women with endometriosis [69].\nSince transcription factors activate or repress genes, it is\npossible that the aberration lies in the expression or func-\ntion of transcription factors. We collected preliminary\ndata showing that in stromal cells isolated from the\nendometrium of baboons with endometriosis, FOXO1\nand HOXA10 had a minimal effect on the IGFBP-1 pro-\nmoter. Interestingly, the cooperative effect of FOXO1 and\nHOXA10 was also repressed. These cells were isolated\nfrom baboons with endometriosis that have been consid-\nered to be subfertile. These intriguing data suggest that the\ncells from animals with endometriosis are different from\nthose of normal baboons. One can speculate that if the\ncooperative action of FOXO1 and HOXA10 does not\noccur in these cells, the upregulation of IGFBP-1 to neces-\nsary levels may not occur, which may somehow be associ-\nated with the infertile status of the animal. Furthermore, if\nthe cooperative action of FOXO1 and HOXA10 does not\noccur, other relevant gene expression may also be inade-\nquate. To date, it is unclear why certain genes are down-\nregulated or abnormally expressed in endometriosis.\nDetermining the mechanisms responsible for the dysreg-\nulation of genes will give us a better understanding of the\npotential causes of infertility associated with endometrio-\nsis.\nConclusions\nThe use of the baboon as an animal model to study uter-\nine receptivity and implantation has been invaluable.\nMuch information on the morphological, biochemical\nand molecular events that occur during early pregnancy\nhas been generated. There is direct evidence of endome-\ntrial modulation by local infusion of CG demonstrating\nthat embryonic signals directly act on the endometrium in\n\nReproductive Biology and Endocrinology 2004, 2 http://www.rbej.com/content/2/1/34\nPage 5 of 6\n(page number not for citation purposes)\nprimates. The implanted embryo promotes decidualiza-\ntion of the endometrium which is essential for the estab-\nlishment of pregnancy and potential transcription factors\nwithin the endometrium that may play a role in this proc-\ness have been identified. With the use of these experimen-\ntal paradigms, it has been shown that endometriosis\naffects uterine receptivity in the baboon. Elucidating the\ncellular and molecular events associated with uterine\nreceptivity and implantation will have significant implica-\ntions in understanding the fundamental causes of implan-\ntation failure and subsequent infertility.\nAcknowledgements\nThese studies were supported by NIH Grants HD 36759 & HD 40093.\nReferences\n1. Hild-Petito S, Donnelly KM, Miller JB, Verhage HG, Fazleabas AT: A\nbaboon (Papio anubis) simulated-pregnant model: cell spe-\ncific expression of insulin-like growth factor binding protein-\n1 (IGFBP-1), type I IGF receptor (IGF-I R) and retinol bind-\ning protein (RBP) in the uterus. 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Tomizawa M, Kumar A, Perrot V, Nakae J, Accili D, Rechler MM,\nKumar A: Insulin inhibits the activati on of transcription by a\n\nPublish with BioMed Central   and  every \nscientist can read your work free of charge\n\"BioMed Central will be the most significant development for \ndisseminating the results of biomedical research in our lifetime.\"\nSir Paul Nurse, Cancer Research UK\nYour research papers will be:\navailable free of charge to the entire biomedical community\npeer reviewed and published immediately upon acceptance\ncited in PubMed and archived on PubMed Central \nyours — you keep the copyright\nSubmit your manuscript here:\nhttp://www.biomedcentral.com/info/publishing_adv.asp\nBioMedcentral\nReproductive Biology and Endocrinology 2004, 2 http://www.rbej.com/content/2/1/34\nPage 6 of 6\n(page number not for citation purposes)\nC-terminal fragment of the fo rkhead transcription factor\nFKHR. 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