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