Lineage allocation and cell polarity during mouse embryogenesis

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Abstract

The first developmental lineage allocation during the generation of the mouse blastocyst is to outer trophoblast or to inner pluriblast (inner cell mass; ICM) cells. This allocation seems to be initiated at the 8-cell stage, when blastomeres polarise. Polarisation is followed by differentiative divisions at the subsequent two cleavage divisions to generate polar outer and non-polar inner 16- and 32-cells. The key events in polarisation are regulated post-translationally through a cell contact-mediated pathway, which imposes a heritable determinant-like organisation on the blastomere cortex. Two proteins in particular, E-cadherin and ezrin, are intimately involved in the generation and stabilisation of developmentally significant information. Transcriptional differences between lineages appear to follow and may coincide with the lineage commitment of cells.

Introduction

Fusion of the mammalian sperm and egg initiates a developmental process leading to the formation of the placenta and the embryo. Thus, an embryo is not an immediate product of fertilisation, but emerges subsequently in a process of “embryo-genesis”. It is paradoxical that the most important developmental event during embryogenesis is the formation of a system of extra-embryonic tissues. These tissues are not only essential for the subsequent support of the embryo but also for the specification of its cells [1], [2], [3], [4]. The cell lineages forming the extra-embryo are allocated in three successive waves in most mammals. First trophoblast is segregated from pluriblast, then, within the pluriblast, hypoblast is segregated from epiblast (Fig. 1), and finally, after implantation, extra-embryonic mesoderm segregates from epiblast at gastrulation. The embryo itself emerges as a small pluripotent cluster of cells [5], [6], [7]. Given this knowledge about early mammalian development, we have suggested that an appropriate name for the product of fertilisation is not embryo but conceptus [5] or embryogen [8]. In this contribution, we use (mainly) the first of these cell allocations, namely pluriblast or trophoblast, to illustrate some basic features and concepts of early mouse development.

Section snippets

A conceptual framework

An enduring question for mammalian development has been whether there exists in the egg any spatially mosaic template of developmental information that directs or influences embryogenesis [8], [9]. It is certainly the case that in the undisturbed embryo up to the blastocyst stage, there is little cellular mixing or migration, and so cytoplasm/cells in different parts of the egg maintain their relative positions [10], [11], [12], [13], [14]. Thus, early relative position relates broadly to later

The cellular mechanisms by which allocation to trophoblast and pluriblast lineages occurs

By the blastocyst stage (32–64-cells; Fig. 1), two tissues are clearly identifiable: an outer layer of trophoblast that secretes and retains blastocoelic fluid and an eccentrically placed group of internalised pluriblast cells forming the inner cell mass (ICM). These two tissue lineages are generated and maintained by two sequential processes.

Cell allocation, fate and commitment

The formation of distinctive inner and outer cells at the transition to the 16-cell stage provides the first clear evidence of cell allocation to trophoblast and pluriblast lineages, since these two subpopulations differ from the moment of their formation in ways that anticipate the differences in properties of mature trophoblast and pluriblast [57]. Since all cells at the 8-cell stage polarise and divide, it seems unlikely that any of them have restricted developmental fates prior to

The molecular basis of trophoblast:pluriblast allocation

The observations reported above focus attention onto two questions. How does asymmetric cell contact between blastomeres at one end of the 8-cell blastomere (or indeed of experimentally exposed 16- or 32-cell inner blastomeres) lead to a stable cytocortical pole at the opposite end of the cell? How does the presence or absence of this apical pole then impose itself so firmly on the developmental fates of the cells of the embryo by directing them towards trophoblast or pluriblast lineages?

Where does transcription fit into trophoblast:pluriblast allocations?

It is now 20 years since detailed protein biosynthetic patterns were used to describe and map temporally the nature and origins of translated transcripts during early mouse development [142], [143], [144], [145], based on seminal RNA studies over the preceding 10 years [146], [147], [148], [149] (these early studies reviewed in [150]). Later studies have refined but broadly confirmed these conclusions (reviewed in [151]) that early zygotic development depends on maternally inherited mRNA and

The importance of temporal events in lineage allocation

Trophoblast:pluriblast cell allocation occurs over 2–3-cell cycles from the early 8-cell to some point in the 32-cell stage, but we do not understand how this time frame is measured or interpreted [173], [174], [175], [176], [177], [178]. We do know that timing differences between individual blastomeres within the same embryo are important. Thus, individual blastomeres within an embryo are asynchronous and this temporal heterogeneity influences lineage allocation. The division of each

To what extent is the trophoblast:pluriblast allocation story representative?

It does seem to be representative of the earliest allocation in other mammals (reviewed recently [6], [52]), so here we consider briefly how it compares with the hypoblast:epiblast allocation in the mouse.

This allocation is thought to occur within the pluriblast population of the ICM during blastocyst expansion [4] (Rossant, this volume). Thus, isolating and culturing ICMs from progressively more expanded blastocysts leads to a decreased incidence of trophoblast generation on the exposed cells

Conclusions

The generation of trophoblast and pluriblast occurs through the radial polarisation of blastomeres at the 8-cell stage. Processes of differential cell division and intercellular adhesion then explain the increasing divergence of the lineages leading to blastocyst biogenesis. The key process of polarisation manifests a number of distinctive features. Those are:

  • (1)

    It is regulated post-translationally, in the mouse on a mix of maternal and zygotic proteins but in other species, in which gene

Acknowledgements

We would like to thank Dee Hughes, Adrian Newman and Ian Bolton for help in the preparation of figures. M.H.J. acknowledges financial support from the Wellcome Trust. J.M.L.M. acknowledges financial support from the British Heart Foundation.

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