Developmental control of the early mammalian embryo: competition among heterogeneous cells that biases cell fate

https://doi.org/10.1016/j.gde.2010.05.006Get rights and content

The temporal and spatial segregation of the two extra-embryonic cell lineages, trophectoderm and primitive endoderm (TE and PE respectively), from the pluripotent epiblast (EPI) during mammalian pre-implantation development are prerequisites for the successful implantation of the blastocyst. The mechanisms underlying these earliest stages of development remain a fertile topic for research and informed debate. In recent years novel roles for various transcription factors, polarity factors and signalling cascades have been uncovered. This mini-review seeks to summarise some of this work and to put it into the context of the regulative nature of early mammalian development and to highlight how the increasing evidence of naturally occurring asymmetries and heterogeneity in the embryo can bias specification of the distinct cell types of the blastocyst.

Introduction

There are two cell fate decisions made before implantation during mammalian development. The first involves the spatial segregation of cells to either the inside of the embryo, the inner cell mass (ICM), or to the outside where they will differentiate to form the first extra-embryonic lineage, the trophectoderm (TE). This relies on series of cell divisions at the 8–16 and 16–32-cell stages, that can be either symmetric, generating two outer presumptive TE daughters, or asymmetric when one daughter remains on the outside and the second is sent inwards to the ICM [1]. The importance of such spatial position within the context of the first cell fate decision forms the basis of the classical ‘Inside–Outside’ hypothesis first put forward over forty years ago [2]. Following this spatial segregation the identity of the cell lineages is steadily established. TE cells differentiate and provide the embryonic tissues with positional cues and support in utero [3, 4, 5, 6, 7] and the ICM retains pluripotency as well as providing cells for the second cell fate decision. This decision results in the generation of the second extra-embryonic tissue, the primitive endoderm (PE) that lies in contact with the blastocyst cavity. Deeper ICM cells retain pluripotency and form the epiblast (EPI) that contributes cells for the embryo proper [8, 9]. Recent advances that describe the molecular determinants involved in each of these two cell fate decisions are discussed below. These recent findings also suggest that it maybe more prescient to consider these two decisions as inter-related given the allocation of TE cells can also by default affect the allocation of potential EPI and PE progenitors to the ICM.

Section snippets

The first cell fate decision

The generation of TE destined outer cells and inner ICM is reliant upon cell internalisation that is in turn dependent upon the orientation of the axis of cell division of 8-cell and 16-cell stage blastomeres. How this division orientation is specified or whether it is random, remains unknown. Before these divisions, 8-cell blastomeres become morphologically polarised along their apical–basal axis [10] and localise specific proteins at either the apical (e.g. aPKC, Par3 [11] and Jam1 [12]) or

The second cell fate decision

Following internalisation, ICM cells either form the pluripotent EPI lineage or differentiate to generate the PE monolayer of cells lining the cavity by the late blastocyst stage. PE formation is known to require a population of ICM cells to upregulate the Gata6 transcription factor [33, 34]. This occurs in a manner mutually exclusive with the pluripotency factor Nanog, in a ‘salt-and-pepper’ pattern of expression in the early blastocyst [35, 36, 37]. Before implantation the Gata6 expressing

First and second cell fate decisions are linked

The observed influence of developmental timing of cell internalisation, that is ‘asymmetric wave of origin’, upon PE and EPI lineage formation [39••], requires a reappraisal of what is meant by the ‘first’ and ‘second’ cell fate decisions. The classical description of the first fate decision as separating TE progenitors from ICM cells and the second as separating EPI from PE should perhaps be viewed from a new perspective. This new vantage point offers the view of a first event that separates

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We are grateful to the Wellcome Trust and the Ministry of Education (6007665801), Czech Republic for supporting our work.

References (47)

  • C. Chazaud et al.

    Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway

    Dev Cell

    (2006)
  • S.A. Morris et al.

    Origin and formation of the first two distinct cell types of the inner cell mass in the mouse embryo

    Proc Natl Acad Sci USA

    (2010)
  • Y. Yamanaka et al.

    FGF signal-dependent segregation of primitive endoderm and epiblast in the mouse blastocyst

    Development

    (2010)
  • A.K. Tarkowski et al.

    Development of blastomeres of mouse eggs isolated at the 4- and 8-cell stage

    J Embryol Exp Morphol

    (1967)
  • M. Yamamoto et al.

    Antagonism between Smad1 and Smad2 signaling determines the site of distal visceral endoderm formation in the mouse embryo

    J Cell Biol

    (2009)
  • M.L. Soares et al.

    Bone morphogenetic protein 4 signaling regulates development of the anterior visceral endoderm in the mouse embryo

    Dev Growth Differ

    (2008)
  • T.A. Rodriguez et al.

    Induction and migration of the anterior visceral endoderm is regulated by the extra-embryonic ectoderm

    Development

    (2005)
  • K.A. Lawson et al.

    Bmp4 is required for the generation of primordial germ cells in the mouse embryo

    Genes Dev

    (1999)
  • R.L. Gardner et al.

    Investigation of the fate of 4–5 day post-coitum mouse inner cell mass cells by blastocyst injection

    J Embryol Exp Morphol

    (1979)
  • R.L. Gardner

    Investigation of cell lineage and differentiation in the extraembryonic endoderm of the mouse embryo

    J Embryol Exp Morphol

    (1982)
  • B. Plusa et al.

    Downregulation of Par3 and aPKC function directs cells towards the ICM in the preimplantation mouse embryo

    J Cell Sci

    (2005)
  • F.C. Thomas et al.

    Contribution of JAM-1 to epithelial differentiation and tight-junction biogenesis in the mouse preimplantation embryo

    J Cell Sci

    (2004)
  • D. Strumpf et al.

    Cdx2 is required for correct cell fate specification and differentiation of trophectoderm in the mouse blastocyst

    Development

    (2005)
  • Cited by (45)

    • Extraembryonic Signals under the Control of MGA, Max, and Smad4 Are Required for Dorsoventral Patterning

      2014, Developmental Cell
      Citation Excerpt :

      This complex pattern of cell fates is communicated during embryogenesis by specialized groups of cells called signaling centers. In vertebrates, the first signaling centers form when the extraembryonic lineages physically segregate from the rest of the embryo (Bruce and Zernicka-Goetz, 2010). This occurs in teleost fish when blastomeres at the embryo margin collapse and release their contents into the adjacent yolk cell, forming a syncytium called the yolk syncytial layer (YSL) (Kimmel and Law, 1985).

    • Polarity-dependent distribution of angiomotin localizes hippo signaling in preimplantation embryos

      2013, Current Biology
      Citation Excerpt :

      The second question is, what is the relationship between the Hippo-regulated mechanism and other mechanisms during initial cell fate specification? Several different mechanisms are known to operate, including very early biases among blastomeres and polarity-dependent asymmetric segregation of mRNAs (see the reviews and references in [50, 51]). Irrespective of the operation of these mechanisms, the experimental manipulation of 16-cell and 32-cell stage embryos demonstrated the complete and partial adjustment of cell fates, respectively, with new cell positions [32].

    View all citing articles on Scopus
    View full text