Nothing Special   »   [go: up one dir, main page]
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Roadmap to embryo implantation: clues from mouse models

Nature Reviews Genetics volume 7, pages 185–199 (2006)Cite this article

Key Points

  • Rapid population growth and infertility are two significant global issues that concern women's health. These issues are greatly influenced by the events of preimplantation embryonic development and implantation.

  • Mammalian preimplantation embryonic development is a dynamic process that encompasses a chain of events from fertilization to implantation. During this period, switching of the genetic programme from the maternal to zygotic genome is characterized by waves of gene expression.

  • Early embryonic cell polarity and lineage differentiation, which are vital to implantation, and continued embryonic growth climax with the onset of blastocyst formation. These processes are coordinated by many transcription factors, including OCT4, SOX2, NANOG, CDX2 and EOMES.

  • Synchronizing preimplantation embryo development up to the blastocyst stage with uterine differentiation to the receptive state is an absolute requirement for successful implantation.

  • Molecular and genetic studies provide evidence for a novel cytokine (leukaemia inhibitory factor)–homeotic (HOXA11/HMX3/MSX1)–morphogen (Indian hedgehog) signalling axis that sets up the window of uterine receptivity for implantation. One significant pathway that influences this axis is progesterone signalling, acting via PRA/FK506 binding protein-4, and oestrogen signalling via ERα.

  • An auto-induction loop of HB-EGF expression, which acts through ErbBs in both the implantation-competent blastocyst and the receptive uterus, amplifies the signalling cascade that initiates the uterine-attachment reaction.

  • Prostaglandin signalling via the cPLA2α/COX2/PPARδ axis and its interaction with the LPA3-mediated pathway ensures normal embryo spacing and on-time implantation in the uterus. A transient delay in on-time implantation creates an adverse ripple effect throughout the course of pregnancy, leading to poor pregnancy outcome. So, implantation serves as a gateway to subsequent embryonic development, and therefore to a full-term offspring.

  • One emerging concept in the field of implantation is that many evolutionarily conserved developmental genes, such fibroblast growth factors, bone morphogenic proteins, Wnts, and Hox-family members, are important in orienting the implantation chamber in the antimesometrial–mesometrial direction and specifying uterine-cell boundaries during postimplantation growth.

  • Understanding the mechanism of preimplantation embryo development and implantation in the uterus will help to alleviate human infertility on the one hand, and rapid population growth on the other.

Abstract

Implantation involves an intricate discourse between the embryo and uterus and is a gateway to further embryonic development. Synchronizing embryonic development until the blastocyst stage with the uterine differentiation that takes place to produce the receptive state is crucial to successful implantation, and therefore to pregnancy outcome. Although implantation involves the interplay of numerous signalling molecules, the hierarchical instructions that coordinate the embryo–uterine dialogue are not well understood. This review highlights our knowledge about the molecular development of preimplantation and implantation and the future challenges of the field. A better understanding of periimplantation biology could alleviate female infertility and help to develop novel contraceptives.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Genes governing the development of the preimplantation mouse embryo.
Figure 2: Gene products participating in embryo implantation.

Similar content being viewed by others

References

  1. Carson, D. D. et al. Embryo implantation. Dev. Biol. 223, 217–237 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Dey, S. K. et al. Molecular cues to implantation. Endocr. Rev. 25, 341–373 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Paria, B. C., Reese, J., Das, S. K. & Dey, S. K. Deciphering the cross-talk of implantation: advances and challenges. Science 296, 2185–2188 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Red-Horse, K. et al. Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface. J. Clin. Invest. 114, 744–754 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Enders, A. C. & Schlafke, S. A morphological analysis of early implantation stages in the rat. Am. J. Anat. 120, 195–226 (1967).

    Article  Google Scholar 

  6. Nothias, J. Y., Majumder, S., Kaneko, K. J. & DePamphilis, M. L. Regulation of gene expression at the beginning of mammalian development. J. Biol. Chem. 270, 22077–22080 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Latham, K. E., Garrels, J. I., Chang, C. & Solter, D. Quantitative analysis of protein synthesis in mouse embryos. I. Extensive reprogramming at the one- and two-cell stages. Development 112, 921–932 (1991).

    CAS  PubMed  Google Scholar 

  8. Shi, C. Z. et al. Protein databases for compacted eight-cell and blastocyst-stage mouse embryos. Mol. Reprod. Dev. 37, 34–47 (1994).

    Article  CAS  PubMed  Google Scholar 

  9. Zimmermann, J. W. & Schultz, R. M. Analysis of gene expression in the preimplantation mouse embryo: use of mRNA differential display. Proc. Natl Acad. Sci. USA 91, 5456–5460 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ko, M. S. et al. Large-scale cDNA analysis reveals phased gene expression patterns during preimplantation mouse development. Development 127, 1737–1749 (2000).

    PubMed  Google Scholar 

  11. Hamatani, T., Carter, M. G., Sharov, A. A. & Ko, M. S. Dynamics of global gene expression changes during mouse preimplantation development. Dev. Cell 6, 117–131 (2004). This study, together with the work described in reference 12, shows that mouse preimplantation embryo development is a dynamic molecular process that is governed by waves of gene expression.

    Article  CAS  PubMed  Google Scholar 

  12. Wang, Q. T. et al. A genome-wide study of gene activity reveals developmental signaling pathways in the preimplantation mouse embryo. Dev. Cell 6, 133–144 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Zeng, F., Baldwin, D. A. & Schultz, R. M. Transcript profiling during preimplantation mouse development. Dev. Biol. 272, 483–496 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Tong, Z. B. et al. Mater, a maternal effect gene required for early embryonic development in mice. Nature Genet. 26, 267–268 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Johnson, M. H. & McConnell, J. M. Lineage allocation and cell polarity during mouse embryogenesis. Semin. Cell Dev. Biol. 15, 583–597 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Rossant, J. Lineage development and polar asymmetries in the peri-implantation mouse blastocyst. Semin. Cell Dev. Biol. 15, 573–581 (2004).

    Article  PubMed  Google Scholar 

  17. Nichols, J. et al. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95, 379–391 (1998). This study shows that expression of Oct4 in inside cells of mouse preimplantation embryos is required for the generation of pluripotent cells. The other key molecules for cell-lineage differentiation during preimplantation development are described in references 18–24.

    Article  CAS  PubMed  Google Scholar 

  18. Avilion, A. A. et al. Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev. 17, 126–140 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Niwa, H., Miyazaki, J. & Smith, A. G. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nature Genet. 24, 372–376 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Mitsui, K. et al. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113, 631–642 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Chambers, I. et al. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113, 643–655 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Boyer, L. A. et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122, 947–956 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Strumpf, D. et al. Cdx2 is required for correct cell fate specification and differentiation of trophectoderm in the mouse blastocyst. Development 132, 2093–2102 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Russ, A. P. et al. Eomesodermin is required for mouse trophoblast development and mesoderm formation. Nature 404, 95–99 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Paria, B. C., Huet-Hudson, Y. M. & Dey, S. K. Blastocyst's state of activity determines the “window” of implantation in the receptive mouse uterus. Proc. Natl Acad. Sci. USA 90, 10159–10162 (1993). This study, which uses a delayed-implantation mouse model, showed for the first time that the receptive state of the uterus alone is not sufficient for successful implantation, but that blastocysts must also achieve implantation competency. The differential roles of oestrogen and catecholoestrogens in establishing the window of implantation are highlighted in references 26 and 32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ma, W. G., Song, H., Das, S. K., Paria, B. C. & Dey, S. K. Estrogen is a critical determinant that specifies the duration of the window of uterine receptivity for implantation. Proc. Natl Acad. Sci. USA 100, 2963–2968 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lopes, F. L., Desmarais, J. A. & Murphy, B. D. Embryonic diapause and its regulation. Reproduction 128, 669–678 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Renfree, M. B. & Shaw, G. Diapause. Annu. Rev. Physiol. 62, 353–375 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Hamatani, T. et al. Global gene expression analysis identifies molecular pathways distinguishing blastocyst dormancy and activation. Proc. Natl Acad. Sci. USA 101, 10326–10331 (2004). This study analyses global gene expression in dormant and activated mouse blastocysts, providing evidence that gene-expression patterns are distinct at these two different physiological states of the embryo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Paria, B. C., Das, S. K., Andrews, G. K. & Dey, S. K. Expression of the epidermal growth factor receptor gene is regulated in mouse blastocysts during delayed implantation. Proc. Natl Acad. Sci. USA 90, 55–59 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Raab, G. et al. Mouse preimplantation blastocysts adhere to cells expressing the transmembrane form of heparin-binding EGF-like growth factor. Development 122, 637–645 (1996).

    CAS  PubMed  Google Scholar 

  32. Paria, B. C. et al. Coordination of differential effects of primary estrogen and catecholestrogen on two distinct targets mediates embryo implantation in the mouse. Endocrinology 139, 5235–5246 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Guo, Y. et al. N–acylphosphatidylethanolamine-hydrolyzing phospholipase D is an important determinant of uterine anandamide levels during implantation. J. Biol. Chem. 280, 23429–23432 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Paria, B. C., Das, S. K. & Dey, S. K. The preimplantation mouse embryo is a target for cannabinoid ligand-receptor signaling. Proc. Natl Acad. Sci. USA 92, 9460–9464 (1995). This work provided the first evidence for the presence of the G-protein-coupled cannabinoid receptors CB1 and CB2 in preimplantation mouse embryos. The differential roles of endocannabinoids in embryo–uterine interactions during implantation are further illustrated in references 33 and 35–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang, H. et al. Aberrant cannabinoid signaling impairs oviductal transport of embryos. Nature Med. 10, 1074–1080 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Wang, H. et al. Differential G protein-coupled cannabinoid receptor signaling by anandamide directs blastocyst activation for implantation. Proc. Natl Acad. Sci. USA 100, 14914–14919 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Paria, B. C. et al. Dysregulated cannabinoid signaling disrupts uterine receptivity for embryo implantation. J. Biol. Chem. 276, 20523–20528 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Wang, J., Mayernik, L., Schultz, J. F. & Armant, D. R. Acceleration of trophoblast differentiation by heparin-binding EGF-like growth factor is dependent on the stage-specific activation of calcium influx by ErbB receptors in developing mouse blastocysts. Development 127, 33–44 (2000).

    CAS  PubMed  Google Scholar 

  39. Stachecki, J. J. & Armant, D. R. Transient release of calcium from inositol 1,4,5-trisphosphate-specific stores regulates mouse preimplantation development. Development 122, 2485–2496 (1996).

    CAS  PubMed  Google Scholar 

  40. Wang, Y. et al. Entire mitogen activated protein kinase (MAPK) pathway is present in preimplantation mouse embryos. Dev. Dyn. 231, 72–87 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Riley, J. K. et al. The PI3K/Akt pathway is present and functional in the preimplantation mouse embryo. Dev. Biol. 284, 377–386 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Lubahn, D. B. et al. Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc. Natl Acad. Sci. USA 90, 11162–11166 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Curtis, S. W., Clark, J., Myers, P. & Korach, K. S. Disruption of estrogen signaling does not prevent progesterone action in the estrogen receptor a knockout mouse uterus. Proc. Natl Acad. Sci. USA 96, 3646–3651 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Paria, B. C., Tan, J., Lubahn, D. B., Dey, S. K. & Das, S. K. Uterine decidual response occurs in estrogen receptor-a-deficient mice. Endocrinology 140, 2704–2710 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Lydon, J. P. et al. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev. 9, 2266–2278 (1995).

    Article  CAS  PubMed  Google Scholar 

  46. Mulac-Jericevic, B., Mullinax, R. A., DeMayo, F. J., Lydon, J. P. & Conneely, O. M. Subgroup of reproductive functions of progesterone mediated by progesterone receptor-B-isoform. Science 289, 1751–1754 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Song, H., Lim, H., Das, S. K., Paria, B. C. & Dey, S. K. Dysregulation of EGF family of growth factors and COX-2 in the uterus during the preattachment and attachment reactions of the blastocyst with the luminal epithelium correlates with implantation failure in LIF-deficient mice. Mol. Endocrinol. 14, 1147–1161 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Stewart, C. L. et al. Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature 359, 76–79 (1992). This study provided the first evidence that Lif is expressed in mouse uterine glands and is essential for implantation. The stromal expression of Lif surrounding the blastocyst at the time of attachment was also found to be important for implantation, as described in reference 47.

    Article  CAS  PubMed  Google Scholar 

  49. Ernst, M. et al. Defective gp130-mediated signal transducer and activator of transcription (STAT) signaling results in degenerative joint disease, gastrointestinal ulceration, and failure of uterine implantation. J. Exp. Med. 194, 189–203 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Benson, G. V. et al. Mechanisms of reduced fertility in Hoxa-10 mutant mice: uterine homeosis and loss of maternal Hoxa-10 expression. Development 122, 2687–2696 (1996).

    CAS  PubMed  Google Scholar 

  51. Hsieh-Li, H. M. et al. Hoxa 11 structure, extensive antisense transcription, and function in male and female fertility. Development 121, 1373–1385 (1995).

    CAS  PubMed  Google Scholar 

  52. Lim, H., Ma, L., Ma, W. G., Maas, R. L. & Dey, S. K. Hoxa-10 regulates uterine stromal cell responsiveness to progesterone during implantation and decidualization in the mouse. Mol. Endocrinol. 13, 1005–1017 (1999).

    Article  CAS  PubMed  Google Scholar 

  53. Satokata, I., Benson, G. & Maas, R. Sexually dimorphic sterility phenotypes in Hoxa10-deficient mice. Nature 374, 460–463 (1995). This paper was the first to show female infertility in mice that lack Hoxa10 . It was later shown that defective decidualization is the cause of this female infertility, as described in references 50 and 52.

    Article  CAS  PubMed  Google Scholar 

  54. Daikoku, T. et al. Uterine Msx-1 and Wnt4 signaling becomes aberrant in mice with the loss of leukemia inhibitory factor or Hoxa-10: evidence for a novel cytokine-homeobox-Wnt signaling in implantation. Mol. Endocrinol. 18, 1238–1250 (2004). This work was the first to provide evidence that cytokines, homeotic proteins and morphogens in the mouse uterus constitute a molecular circuitry that is crucial to implantation.

    Article  CAS  PubMed  Google Scholar 

  55. Gendron, R. L. et al. Abnormal uterine stromal and glandular function associated with maternal reproductive defects in Hoxa-11 null mice. Biol. Reprod. 56, 1097–1105 (1997).

    Article  CAS  PubMed  Google Scholar 

  56. Taylor, H. S., Arici, A., Olive, D. & Igarashi, P. HOXA10 is expressed in response to sex steroids at the time of implantation in the human endometrium. J. Clin. Invest. 101, 1379–1384 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wang, W., Van De Water, T. & Lufkin, T. Inner ear and maternal reproductive defects in mice lacking the Hmx3 homeobox gene. Development 125, 621–634 (1998).

    CAS  PubMed  Google Scholar 

  58. Borthwick, J. M. et al. Determination of the transcript profile of human endometrium. Mol. Hum. Reprod. 9, 19–33 (2003).

    Article  CAS  PubMed  Google Scholar 

  59. Carson, D. D. et al. Changes in gene expression during the early to mid-luteal (receptive phase) transition in human endometrium detected by high-density microarray screening. Mol. Hum. Reprod. 8, 871–879 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. Kao, L. C. et al. Global gene profiling in human endometrium during the window of implantation. Endocrinology 143, 2119–2138 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Mirkin, S. et al. In search of candidate genes critically expressed in the human endometrium during the window of implantation. Hum. Reprod. 20, 2104–2117 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Riesewijk, A. et al. Gene expression profiling of human endometrial receptivity on days LH+2 versus LH+7 by microarray technology. Mol. Hum. Reprod. 9, 253–264 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. Satokata, I. & Maas, R. Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nature Genet. 6, 348–356 (1994).

    Article  CAS  PubMed  Google Scholar 

  64. Takamoto, N., Zhao, B., Tsai, S. Y. & DeMayo, F. J. Identification of Indian hedgehog as a progesterone-responsive gene in the murine uterus. Mol. Endocrinol. 16, 2338–2348 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Matsumoto, H., Zhao, X., Das, S. K., Hogan, B. L. & Dey, S. K. Indian hedgehog as a progesterone-responsive factor mediating epithelial-mesenchymal interactions in the mouse uterus. Dev. Biol. 245, 280–290 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Paria, B. C. et al. Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors. Proc. Natl Acad. Sci. USA 98, 1047–1052 (2001). This article provides a comprehensive account of the expression of morphogens, including HH, BMP, WNT and FGF signalling in the mouse uterus during the periimplantation period. The evidence that HH signalling in the uterine epithelial–mesenchymal interaction is important for implantation was later reported in references 64 and 65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Parr, B. A. & McMahon, A. P. Sexually dimorphic development of the mammalian reproductive tract requires Wnt-7a. Nature 395, 707–710 (1998).

    Article  CAS  PubMed  Google Scholar 

  68. Daikoku, T. et al. Proteomic analysis identifies immunophilin FK506 binding protein 4 (FKBP52) as a downstream target of Hoxa10 in the periimplantation mouse uterus. Mol. Endocrinol. 19, 683–697 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Tranguch, S. et al. Cochaperone immunophilin FKBP52 is critical to uterine receptivity for embryo implantation. Proc. Natl Acad. Sci. USA 102, 14326–14331 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Das, S. K. et al. Heparin-binding EGF-like growth factor gene is induced in the mouse uterus temporally by the blastocyst solely at the site of its apposition: a possible ligand for interaction with blastocyst EGF-receptor in implantation. Development 120, 1071–1083 (1994). The role of HB-EGF as an early initiator of molecular crosstalk between the blastocyst and uterus before attachment was first illustrated in this study.

    CAS  PubMed  Google Scholar 

  71. Iwamoto, R. et al. Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function. Proc. Natl Acad. Sci. USA 100, 3221–3226 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Chobotova, K. et al. Heparin-binding epidermal growth factor and its receptor ErbB4 mediate implantation of the human blastocyst. Mech. Dev. 119, 137–144 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Genbacev, O. D. et al. Trophoblast L-selectin-mediated adhesion at the maternal-fetal interface. Science 299, 405–408 (2003). This study shows that, in humans, selectin oligosaccharide ligands are expressed in the receptive uterine lining, while the Tr cell surface is decorated with L-selectin. Further evidence indicates that this ligand–receptor signalling is important for human implantation.

    Article  CAS  PubMed  Google Scholar 

  74. Fouladi-Nashta, A. A. et al. Characterization of the uterine phenotype during the peri-implantation period for LIF-null, MF1 strain mice. Dev. Biol. 281, 1–21 (2005).

    Article  CAS  PubMed  Google Scholar 

  75. Lim, H. et al. Multiple female reproductive failures in cyclooxygenase 2-deficient mice. Cell 91, 197–208 (1997). This study shows that ovulation, fertilization, implantation and decidualization are defective in mice lacking COX2-derived prostaglandins.

    Article  CAS  PubMed  Google Scholar 

  76. Lim, H. et al. Cyclo-oxygenase-2-derived prostacyclin mediates embryo implantation in the mouse via PPARδ. Genes Dev. 13, 1561–1574 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wang, H. et al. Rescue of female infertility from the loss of cyclooxygenase-2 by compensatory up-regulation of cyclooxygenase-1 is a function of genetic makeup. J. Biol. Chem. 279, 10649–10658 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Kim, J. J. et al. Expression of cyclooxygenase-1 and-2 in the baboon endometrium during the menstrual cycle and pregnancy. Endocrinology 140, 2672–2678 (1999).

    Article  CAS  PubMed  Google Scholar 

  79. Song, H. et al. Cytosolic phospholipase A2α is crucial for “on-time” embryo implantation that directs subsequent development. Development 129, 2879–2889 (2002). This work shows that mouse uteri that lack cPLA2α transiently defer on-time implantation, creating an adverse ripple effect throughout the course of pregnancy and leading to poor pregnancy outcome. A similar phenotype is observed in lpA3 -null mice, as reported in reference 80. The importance of on-time implantation in human pregnancy outcome is presented in reference 81.

    CAS  PubMed  Google Scholar 

  80. Ye, X. et al. LPA3-mediated lysophosphatidic acid signalling in embryo implantation and spacing. Nature 435, 104–108 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Wilcox, A. J., Baird, D. D. & Weinberg, C. R. Time of implantation of the conceptus and loss of pregnancy. N. Engl. J. Med. 340, 1796–1799 (1999).

    Article  CAS  PubMed  Google Scholar 

  82. Hogan, B. L. Bone morphogenetic proteins: multifunctional regulators of vertebrate development. Genes Dev. 10, 1580–1594 (1996).

    Article  CAS  PubMed  Google Scholar 

  83. Pfendler, K. C., Yoon, J., Taborn, G. U., Kuehn, M. R. & Iannaccone, P. M. Nodal and bone morphogenetic protein 5 interact in murine mesoderm formation and implantation. Genesis 28, 1–14 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Arikawa, T., Omura, K. & Morita, I. Regulation of bone morphogenetic protein-2 expression by endogenous prostaglandin E2 in human mesenchymal stem cells. J. Cell. Physiol. 200, 400–406 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. Matsumoto, H. et al. Cyclooxygenase-2 differentially directs uterine angiogenesis during implantation in mice. J. Biol. Chem. 277, 29260–29267 (2002). This study shows that COX2-derived prostaglandins coordinate VEGF and angiopoietin signalling during angiogenesis in the mouse deciduum — a process that is required for the establishment of pregnancy.

    Article  CAS  PubMed  Google Scholar 

  86. Paria, B. C. & Dey, S. K. Preimplantation embryo development in vitro: cooperative interactions among embryos and role of growth factors. Proc. Natl Acad. Sci. USA 87, 4756–4760 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Leach, R. E. et al. Pre-eclampsia and expression of heparin-binding EGF-like growth factor. Lancet 360, 1215–1219 (2002).

    Article  CAS  PubMed  Google Scholar 

  88. National Institutes of Health. Stem Cells: Scientific Progress and Future Research Directions. Stem Cell Information [online], http://stemcells.nih.gov/info/scireport (2001).

  89. Gardner, R. L. Specification of embryonic axes begins before cleavage in normal mouse development. Development 128, 839–847 (2001).

    CAS  PubMed  Google Scholar 

  90. Fujimori, T., Kurotaki, Y., Miyazaki, J. & Nabeshima, Y. Analysis of cell lineage in two- and four-cell mouse embryos. Development 130, 5113–5122 (2003).

    Article  CAS  PubMed  Google Scholar 

  91. Piotrowska, K., Wianny, F., Pedersen, R. A. & Zernicka-Goetz, M. Blastomeres arising from the first cleavage division have distinguishable fates in normal mouse development. Development 128, 3739–3748 (2001).

    CAS  PubMed  Google Scholar 

  92. Piotrowska, K. & Zernicka-Goetz, M. Role for sperm in spatial patterning of the early mouse embryo. Nature 409, 517–521 (2001).

    Article  CAS  PubMed  Google Scholar 

  93. Gardner, R. L. The early blastocyst is bilaterally symmetrical and its axis of symmetry is aligned with the animal–vegetal axis of the zygote in the mouse. Development 124, 289–301 (1997). This article proposes the concept of the embryonic axis and cell polarity during mouse preimplantation development. The ongoing debate on this subject is further highlighted in references 89–92,96,101,107 and 108.

    CAS  PubMed  Google Scholar 

  94. Piotrowska-Nitsche, K., Perea-Gomez, A., Haraguchi, S. & Zernicka-Goetz, M. Four-cell stage mouse blastomeres have different developmental properties. Development 132, 479–490 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. Piotrowska-Nitsche, K. & Zernicka-Goetz, M. Spatial arrangement of individual 4-cell stage blastomeres and the order in which they are generated correlate with blastocyst pattern in the mouse embryo. Mech. Dev. 122, 487–500 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. Plusa, B. et al. The first cleavage of the mouse zygote predicts the blastocyst axis. Nature 434, 391–395 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Surani, M. A. & Barton, S. C. Spatial distribution of blastomeres is dependent on cell division order and interactions in mouse morulae. Dev. Biol. 102, 335–343 (1984).

    Article  CAS  PubMed  Google Scholar 

  98. Garbutt, C. L., Johnson, M. H. & George, M. A. When and how does cell division order influence cell allocation to the inner cell mass of the mouse blastocyst? Development 100, 325–332 (1987).

    CAS  PubMed  Google Scholar 

  99. Alarcon, V. B. & Marikawa, Y. Unbiased contribution of the first two blastomeres to mouse blastocyst development. Mol. Reprod. Dev. 72, 354–361 (2005).

    Article  CAS  PubMed  Google Scholar 

  100. Chroscicka, A., Komorowski, S. & Maleszewski, M. Both blastomeres of the mouse 2-cell embryo contribute to the embryonic portion of the blastocyst. Mol. Reprod. Dev. 68, 308–312 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Motosugi, N., Bauer, T., Polanski, Z., Solter, D. & Hiiragi, T. Polarity of the mouse embryo is established at blastocyst and is not prepatterned. Genes Dev. 19, 1081–1092 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Rossant, J. & Tam, P. P. Emerging asymmetry and embryonic patterning in early mouse development. Dev. Cell 7, 155–164 (2004).

    Article  CAS  PubMed  Google Scholar 

  103. Zernicka-Goetz, M. First cell fate decisions and spatial patterning in the early mouse embryo. Semin. Cell Dev. Biol. 15, 563–572 (2004).

    Article  CAS  PubMed  Google Scholar 

  104. Plusa, B., Grabarek, J. B., Piotrowska, K., Glover, D. M. & Zernicka-Goetz, M. Site of the previous meiotic division defines cleavage orientation in the mouse embryo. Nature Cell Biol. 4, 811–815 (2002).

    Article  CAS  PubMed  Google Scholar 

  105. Plusa, B., Piotrowska, K. & Zernicka-Goetz, M. Sperm entry position provides a surface marker for the first cleavage plane of the mouse zygote. Genesis 32, 193–198 (2002).

    Article  PubMed  Google Scholar 

  106. Davies, T. J. & Gardner, R. L. The plane of first cleavage is not related to the distribution of sperm components in the mouse. Hum. Reprod. 17, 2368–2379 (2002).

    Article  CAS  PubMed  Google Scholar 

  107. Hiiragi, T. & Solter, D. First cleavage plane of the mouse egg is not predetermined but defined by the topology of the two apposing pronuclei. Nature 430, 360–364 (2004).

    Article  CAS  PubMed  Google Scholar 

  108. Louvet-Vallee, S., Vinot, S. & Maro, B. Mitotic spindles and cleavage planes are oriented randomly in the two-cell mouse embryo. Curr. Biol. 15, 464–469 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Ain, R., Dai, G., Dunmore, J. H., Godwin, A. R. & Soares, M. J. A prolactin family paralog regulates reproductive adaptations to a physiological stressor. Proc. Natl Acad. Sci. USA 101, 16543–16548 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Cheon, Y. P. et al. A genomic approach to identify novel progesterone receptor regulated pathways in the uterus during implantation. Mol. Endocrinol. 16, 2853–2871 (2002).

    Article  CAS  PubMed  Google Scholar 

  111. Reese, J. et al. Global gene expression analysis to identify molecular markers of uterine receptivity and embryo implantation. J. Biol. Chem. 276, 44137–44145 (2001).

    Article  CAS  PubMed  Google Scholar 

  112. Reyzer, M. L. & Caprioli, R. M. MALDI mass spectrometry for direct tissue analysis: a new tool for biomarker discovery. J. Proteome Res. 4, 1138–1142 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Ralston, A. & Rossant, J. Genetic regulation of stem cell origins in the mouse embryo. Clin. Genet. 68, 106–112 (2005).

    Article  CAS  PubMed  Google Scholar 

  114. Branford, W. W., Benson, G. V., Ma, L., Maas, R. L. & Potter, S. S. Characterization of Hoxa-10/Hoxa-11 transheterozygotes reveals functional redundancy and regulatory interactions. Dev. Biol. 224, 373–387 (2000).

    Article  CAS  PubMed  Google Scholar 

  115. Mericskay, M., Kitajewski, J. & Sassoon, D. Wnt5a is required for proper epithelial–mesenchymal interactions in the uterus. Development 131, 2061–2072 (2004).

    Article  CAS  PubMed  Google Scholar 

  116. Shindo, T. et al. ADAMTS-1: a metalloproteinase-disintegrin essential for normal growth, fertility, and organ morphology and function. J. Clin. Invest. 105, 1345–1352 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Simmen, R. C. et al. Subfertility, uterine hypoplasia, and partial progesterone resistance in mice lacking the Kruppel-like factor 9/basic transcription element-binding protein-1 (Bteb1) gene. J. Biol. Chem. 279, 29286–29294 (2004).

    Article  CAS  PubMed  Google Scholar 

  118. Fowler, K. J. et al. Uterine dysfunction and genetic modifiers in centromere protein B-deficient mice. Genome Res 10, 30–41 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Panda, D. K. et al. Targeted ablation of the 25-hydroxyvitamin D 1α-hydroxylase enzyme: evidence for skeletal, reproductive, and immune dysfunction. Proc. Natl. Acad Sci. USA 98, 7498–7503 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Baker, J. et al. Effects of an Igf1 gene null mutation on mouse reproduction. Mol. Endocrinol. 10, 903–918 (1996).

    CAS  PubMed  Google Scholar 

  121. Smith, C. L. et al. Genetic ablation of the steroid receptor coactivator-ubiquitin ligase, E6-AP, results in tissue-selective steroid hormone resistance and defects in reproduction. Mol. Cell Biol. 22, 525–535 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Yoshizawa, T. et al. Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nature Genet. 16, 391–396 (1997).

    Article  CAS  PubMed  Google Scholar 

  123. Igakura, T. et al. A null mutation in basigin, an immunoglobulin superfamily member, indicates its important roles in peri-implantation development and spermatogenesis. Dev. Biol. 194, 152–165 (1998).

    Article  CAS  PubMed  Google Scholar 

  124. Kuno, N. et al. Female sterility in mice lacking the basigin gene, which encodes a transmembrane glycoprotein belonging to the immunoglobulin superfamily. FEBS Lett. 425, 191–194 (1998).

    Article  CAS  PubMed  Google Scholar 

  125. Barak, Y. et al. Effects of peroxisome proliferator-activated receptor δ on placentation, adiposity, and colorectal cancer. Proc. Natl Acad. Sci USA 99, 303–308 (2002).

    Article  CAS  PubMed  Google Scholar 

  126. Robb, L. et al. Infertility in female mice lacking the receptor for interleukin 11 is due to a defective uterine response to implantation. Nature Med 4, 303–308 (1998).

    Article  CAS  PubMed  Google Scholar 

  127. Bilinski, P., Roopenian, D. & Gossler, A. Maternal IL-11Rα function is required for normal decidua and fetoplacental development in mice. Genes Dev. 12, 2234–2243 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Meissner, A. & Jaenisch, R. Generation of nuclear transfer-derived pluripotent ES cells from cloned Cdx2-deficient blastocysts. Nature 439, 212–215 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. Niwa, H. et al. Interaction between Oct3/4 and Cdx2 determines trophectoderm differentiation. Cell 123, 917–929 (2005).

    Article  CAS  PubMed  Google Scholar 

  130. Gore, A. V. et al. The zebrafish dorsal axis is apparent at the four-cell stage. Nature 438, 1030–1035 (2005).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We regret that page limitations precluded us from citing numerous relevant references. The authors' work embodied in this article was supported in parts by NIH Grants to S.K.D. S.K.D. is the recipient of Method to Extend Research in Time (MERIT) Awards from the National Institute on Drug Abuse (NIDA) and the National Institute of Child Health and Human Development (NICHD). H.W. is the recipient of Solvay/Mortola Research Award from the Society for Gynecologic Investigation. We thank S. Tranguch for critical reading of the manuscript.

Author information

Authors and Affiliations

  1. Departments of Pediatrics, Division of Reproductive and Developmental Biology, Cell & Developmental Biology, and Pharmacology, Vanderbilt University Medical Center, Nashville, 37232, Tennessee, USA

    Haibin Wang & Sudhansu K. Dey

Authors
  1. Haibin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sudhansu K. Dey
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sudhansu K. Dey.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Related links

Related links

FURTHER INFORMATION

Sudhansu K. Dey's homepage

NIA Mouse cDNA Project

Glossary

Blastocyst

An embryonic stage in mammals that is derived from a morula and is comprised of a fluid-filled cavity (blastocoel) and two cell types, the inner cell mass and the trophectoderm.

Compaction

An embryonic state in which the cells of the morula are flattened and cell outlines are not clearly distinguishable.

Morula

A cluster of blastomeres that results from the early cleavages of a zygote.

Zona pellucida

An outer shell composed of glycoproteins that encircles oocytes or preimplantation embryos.

Trophectoderm

The outer layer of the blastocyst that is the progenitor of future trophoblast cell types.

Inner cell mass

Cells that are present inside the blastocyst. These cells are pluripotent and give rise to the embryo proper (that is, the cells that are not destined to become the placenta).

Syncytial trophoblast

The syncytial multinucleated outer layer of the trophoblast.

mRNA differential display

A technique for detecting genes that are expressed only under specific conditions; it involves isolating mRNA from two or more cell populations and comparing their transcript-expression levels.

Pseudopregnancy

A condition similar to pregnancy, without the presence of a fertilized egg, which is produced by sterile mating or hormone treatment.

Cavitation

The creation of a hollow space that appears within the early-cleaving embryos to form a blastocyst.

Embryonic stem cells

(ES cells). Stem cells have the dual capacity to self-replicate and differentiate into several specialized derivatives. ES cells are pluripotent cells that are derived from pre-implantation-stage (usually blastocyst) mammalian embryos. Mouse ES cells can be propagated and manipulated in vitro, yet still retain their pluripotency.

Polar body

The structure that is extruded from the oocyte during meiosis, which contains one haploid set of chromosomes.

Window of implantation

A limited time period when the uterine environment is conducive to supporting blastocyst growth, attachment and the subsequent events of implantation.

Delayed implantation

A state of suspended animation of the blastocyst, characterized by halted growth and postponement of implantation. In mice, ovariectomy on day 4 morning of pregnancy, before ovarian oestrogen secretion, initiates blastocyst dormancy, which can last for many days if treated with P4; an oestrogen injection rapidly activates blastocysts and initiates their implantation.

Blastocyst activation

The event that leads to the competency of the blastocyst to implant.

Hypoplastic

Refers to an underdeveloped tissue or organ.

Decidualization

Transformation of stromal cells into morphologically and functionally distinct cells. Part of decidualized tissue is shed at parturition.

Attachment

A process by which the blastocyst trophectoderm is brought into physical and physiological contact with the uterine luminal epithelium.

Myometrium

The muscular outer layer of the uterus, which is comprised of longitudinal and circular muscle fibers.

Endometrium

The inner lining of the uterus; it is primarily comprised of stromal cells (the supporting tissue of an organ) and epithelial cells of both luminal and glandular types. Part of the endometrium is shed during menstruation.

Basal lamina

A thin sheet of proteoglycans and glycoproteins that are secreted by cells as an extracellular matrix. It is also called the basement membrane and influences cell polarity, differentiation and migration.

Decidual cells

In the mouse, the cells that surround the implanting blastocyst.

Oedema

Fluid accumulation in the intercellular tissue spaces.

Luminal closure

The closure of the uterine lumen, resulting in closer contact between the luminal epithelial linings; this step is essential for blastocyst attachment.

Integrins

A family of receptors for various extracellular-matrix ligands that modulate cell–cell adhesion and signal transduction. Each integrin has two subunits, α and β, and each αβ combination has a unique binding specificity and unique signalling properties.

Selectins

A group of cell-adhesion molecules, including L-selectin, E-selectin and P-selectin, that bind to carbohydrates.

Galectins

A family of lectins with galactose-binding ability.

Trophinin–tastin–bystin complex

A homophilic cell-adhesion complex that is comprised of membrane–cytoplasmic proteins.

Prostaglandins

(PG). Vasoactive lipid mediators that are implicated in various pathophysiological processes, including vascular permeability, angiogenesis and cell migration.

Placenta previa

A condition in humans in which the placenta is situated close to or covering the cervix.

Hemochorial placentation

The process by which maternal blood comes in direct contact with the trophoblast.

MALDI mass spectrometry

(Matrix-assisted laser desorption/ionization mass spectrometry). It is based on the co-crystallization of a test compound with an ultraviolet-light-absorbing matrix, which allows ionization using laser excitation to determine the mass of the test compound.

Preeclampsia

The development of hypertension with proteinuria (excess protein in urine) and/or oedema during pregnancy; early onset occurs from defective trophoblast function.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, H., Dey, S. Roadmap to embryo implantation: clues from mouse models. Nat Rev Genet 7, 185–199 (2006). https://doi.org/10.1038/nrg1808

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg1808

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing