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  • Review Article
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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.

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

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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.

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  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

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  1. Haibin Wang
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Correspondence to Sudhansu K. Dey.

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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.

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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

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