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Making a commitment: cell lineage allocation and axis patterning in the early mouse embryo

Nature Reviews Molecular Cell Biology volume 10, pages 91–103 (2009)Cite this article

Key Points

  • During development, cells become progressively restricted in their lineage choices. The allocation of cells to a specific lineage is regulated by the activities of key signalling pathways and developmentally regulated transcription factors.

  • The first binary cell lineage decision, between the trophectoderm (TE) and the inner cell mass (ICM), is governed by the exclusive expression of caudal-type homeobox protein 2 (CDX2) and octamere-binding transcription factor 3/4 (OCT3/4; also known as POU5F1) in TE or ICM, respectively. The ICM is further subdivided into the primitive endoderm and epiblast by expression of GATA-binding factor 6 (GATA6) and nanog.

  • Signals from the extraembryonic tissues, namely the TE and primitive endoderm, have instructive roles in setting up the embryonic axes and are the source of growth factors and their antagonists that regulate cell type specification in epiblast derivatives during gastrulation.

  • The primitive streak is the site where the mesoderm and definitive endoderm are formed and it is induced in response to Wnt and transforming growth factor β (TGFβ)–nodal signalling.

  • At the primitive streak, cells are allocated to specific fates according to their spatio-temporal position in the streak. The positional information reflects differences in signalling strength of fibroblast growth factor 8 (FGF8), WNT3 or WNT3A and nodal–SMAD2 and SMAD3 and bone morphogenetic protein 4 (BMP4), which are integrated to direct cell lineage specification and regulate morphogenesis.

  • Segregation of primordial germ cells (PGCs) from the somatic lineages at gastrulation requires BMP4–SMAD1 and SMAD5 signals from the extraembryonic ectoderm. Primordial germ cells undergo extensive epigenetic reprogramming to maintain pluripotency throughout the life cycle.

Abstract

Genetic studies have identified the key signalling pathways and developmentally regulated transcription factors that govern cell lineage allocation and axis patterning in the early mammalian embryo. Recent advances have uncovered details of the molecular circuits that tightly control cell growth and differentiation in the mammalian embryo from the blastocyst stage, through the establishment of initial anterior–posterior polarity, to gastrulation, when the germ cells are set aside and the three primary germ layers are specified. Relevant studies in lower vertebrates indicate the conservation and divergence of regulatory mechanisms for cell lineage allocation and axis patterning.

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Figure 1: Lineage segregation in the blastocyst.
Figure 2: The proximo–distal axis of the pre-gastrulation embryo is established through reciprocal tissue interactions.
Figure 3: Formation of different cell types at gastrulation.
Figure 4: Epithelial–mesenchymal transition in the primitive streak.
Figure 5: Dose-dependent BMP–SMAD signals are required for germ cell lineage specification.

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Acknowledgements

We thank L. Bikoff for valuable comments on the manuscript. Work in the laboratory is supported by a Programme Grant from the Wellcome Trust. E.J.R. is Principal Fellow of the Wellcome Trust. S.J.A. is supported in part by a Feodor Lynen-Fellowship from the Alexander von Humboldt-Foundation.

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  1. Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK

    Sebastian J. Arnold & Elizabeth J. Robertson

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Glossary

Gastrulation

The embryonic process during which the three germ layers of the embryo are specified.

Blastocyst

The spherical embryo at the time of implantation. The blastocyst consists of the primary tissue types: trophectoderm, epiblast and the primitive endoderm.

Blastomere

The cell type of the early embryo that is generated by cleavage of the zygote.

Inner cell mass

Pluripotent tissue inside the blastocyst that gives rise to the embryo proper and yolk sac tissue.

Trophectoderm

An extraembryonic, outside tissue layer of the early embryo that connects the embryo to the uterus and forms the placenta.

Pluripotency

The ability of a stem cell to give rise to many different cell types.

Primitive endoderm

Extraembryonic tissue that initially covers the epiblast surface and later gives rise to the yolk sac tissue.

Epiblast

The founding tissue of the embryo proper that gives rise to all fetal tissues.

Ectoderm

The founding germ layer of neural tissues, neural crest and skin.

Mesoderm

The middle sheet of mesenchymal cells that forms blood and vasculature, muscle, bone, cartilage and connective tissues. Mesoderm contributes to many cell types of internal organs.

Definitive endoderm

The outside tissue layer that gives rise to the gut tube and associated organs, such as the lungs, liver, pancreas and the intestinal tract.

Primitive streak

The site on the posterior side of the embryo where epiblast cells ingress to form the mesoderm and definitive endoderm.

Epithelial–mesenchymal transition

A process during which cells change their shape from an epithelium to mesenchyme by loss of epithelial cell adhesion properties and epithelial cell polarity.

Morphogen

A signalling molecule that generates dose-dependent morphogenetic responses during development.

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Arnold, S., Robertson, E. Making a commitment: cell lineage allocation and axis patterning in the early mouse embryo. Nat Rev Mol Cell Biol 10, 91–103 (2009). https://doi.org/10.1038/nrm2618

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