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  • Review Article
  • Published:

Making a firm decision: multifaceted regulation of cell fate in the early mouse embryo

Nature Reviews Genetics volume 10, pages 467–477 (2009)Cite this article

Key Points

  • This Review aims to collate our current understanding of the molecular processes that govern the two necessary cell fate decisions made by the developing preimplantation embryo until the blastocyst stage. We revisit some of the 'classical' models put forward and discuss their merit in the light of new discoveries and propose that, far from being exclusive, each model is likely to harbour at least some fundamental truths.

  • We introduce the first cell fate decision that is defined as the cell's choice to either occupy an inner position in the developing embryo and so retain pluripotency or to populate a position on the outside and differentiate into trophectoderm. We discuss the roles of cellular polarization and position in regulating trophectoderm differentiation and focus on the essential trophectoderm transcription factor, CDX2, to highlight these points.

  • In addition, we explore epigenetic components of the first cell fate decision and discuss the origins in developmental bias and asymmetry in CDX2 expression. We conclude by revisiting the three classical models of the first cell fate decision, the early asymmetry, inside–outside and polarization hypotheses, in the context of recent discoveries and argue that each model contains fundamental truths.

  • We introduce the second cell fate decision whereby cells at the surface of the inner cell mass that line the blastocoel cavity become set aside and form the primitive endoderm and are distinct from the deeper inner cells that form the epiblast, which is comprised of progenitor cells for the fetus proper.

  • We review the two classical models of primitive endoderm formation, the positional induction and cell sorting hypotheses, and discuss the experimental evidence in support of these. In the context of these two classical models, we introduce new evidence detailing the importance of the developmental stage in which inner cells are originally derived on the formation of primitive endoderm and epiblast cell populations. Given these new data, we propose a third refined model of the second cell fate decision that we term the social mobility model.

Abstract

The preimplantation mammalian embryo offers a striking opportunity to address the question of how and why apparently identical cells take on separate fates. Two cell fate decisions are taken before the embryo implants; these decisions set apart a group of pluripotent cells, progenitors for the future body, from the distinct extraembryonic lineages of trophectoderm and primitive endoderm. New molecular, cellular and developmental insights reveal the interplay of transcriptional regulation, epigenetic modifications, cell position and cell polarity in these two fate decisions in the mouse. We discuss how mechanisms proposed in previously distinct models might work in concert to progressively reinforce cell fate decisions through feedback loops.

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Figure 1: Transcriptional regulation and cell fate decisions in preimplantation development.
Figure 2: Transcriptional circuits in the first cell fate decision.
Figure 3: Integration of three hypotheses for the emergence of inside and outside cell differences.
Figure 4: Second cell fate decision — primitive endoderm formation.

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We are grateful to the Wellcome Trust for support.

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  1. The Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK

    Magdalena Zernicka-Goetz, Samantha A. Morris & Alexander W. Bruce

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Glossary

Blastocyst

A preimplantation embryo that contains a fluid-filled cavity (the blastocoel), a focal cluster of cells from which the embryo will develop (the inner cell mass) and peripheral trophoblast cells, which form the placenta.

Trophectoderm

The outer layer of the blastocyst stage embryo that will give rise to the extraembryonic ectoderm after implantation and will provide the bulk of the embryonic part of the placenta.

Inner cell mass

A small group of undifferentiated cells in the blastocyst, which gives rise to the entire fetus and some of its extraembryonic tissues.

Primitive endoderm

An early differentiated cell type that lines the inner surface of the blastocyst cavity. It gives rise to the visceral and parietal extraembryonic endoderm after implantation.

Epiblast

The epithelial tissue that develops from the inner cell mass of the blastocyst and that gives rise to all three definitive germ layers of the embryo during gastrulation: the ectoderm, mesoderm and endoderm.

Embryonic–abembryonic axis

The side of blastocyst on which the inner cell mass (containing progenitor cells for the body proper) is localized is defined as the embryonic pole, with the opposing pole (containing the cavity) defined as abembryonic. Accordingly, these poles define the embryonic–abembryonic axis.

Chromatin remodelling

Changes in the structural properties of chromatin (either covalent post-translational modifications or architectural properties) that ultimately affect its accessibility to protein factors, such astranscription factors or RNA polymerase, that can result in underlying gene expression changes.

RNA-induced silencing complex

A complex made up of an Argonaute protein and small RNA that inhibits translation of target RNAs through degradative and non-degradative mechanisms.

Blastomere

An early embryonic cell that is derived from the cleavage divisions of a fertilized egg.

Polarization

Generation of morphological and molecular differences along the apical–basal axis of cells such asblastomeres.

Animal pole

The position on the oocyte, and later on the embryo, in which the two asymmetric meiotic divisions take place. The first of these meiotic divisions takes place during oocyte maturation and the second after fertilization, both lead to extrusion of small cells called polar bodies. The second polar body remains attached and marks the animal–vegetal axis.

Vegetal pole

The position on the oocyte, and later on the embryo, opposite where the two asymmetric meiotic divisions take place.

Cavitation

The process by which the fluid-filled vesicular cavity (the blastocoel) is generated in approximately 32-cell stage embryos, forming a morphologically recognizable blastocyst.

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Zernicka-Goetz, M., Morris, S. & Bruce, A. Making a firm decision: multifaceted regulation of cell fate in the early mouse embryo. Nat Rev Genet 10, 467–477 (2009). https://doi.org/10.1038/nrg2564

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