Several hypotheses have been formulated to explain how cells make the first lineage decision during mammalian embryonic development. An overarching mechanism now unifies these disparate models. See Letter p.344
The early mammalian embryo is an exemplar of a self-organizing system — distinct cell lineages are autonomously defined and stereotypically positioned as development progresses. The mechanism underlying formation of these cell lineages has long been elusive. On page 344, Maitre et al.1 find that coordination between the contractility, polarity and position of a cell determines its identity, thereby defining the first lineage decision in the mouse embryo.
During the first stages of mammalian development, the fertilized egg undergoes a series of divisions that produce cells called blastomeres. During the transition from the 8- to the 16-cell stage, different cell lineages arise for the first time. Some blastomeres adopt an internal position and form the inner cell mass (ICM) from which the embryo proper will arise, whereas cells adopting an outer position become the trophectoderm layer2,3 and go on to form the placenta.
Several models have been proposed for the regulation of this first cell-fate decision4. The first, put forward5 in 1967 and later confirmed experimentally6, posited that lineage is determined by the position of blastomeres within the embryo — whether or not they make contact with the external environment. When cell polarity emerged as a major feature of the lineage-specification process, an alternative mechanism was proposed3. At the 8-cell stage, blastomeres become polarized along their apical–basal axis, with certain proteins becoming restricted to the apical domain2,7 (the side of the cell facing towards the outside of the embryo). This hypothesis stated that cells that inherit the apical region at cell division acquire polarity, adopt an outside position and become trophectoderm, whereas those that do not inherit an apical region are internalized and become ICM.
The molecular mechanisms that link cell polarity to the first cell-fate choices remained a mystery for many years. But recently, differential activity of the Hippo signalling pathway was shown to be crucial for the decision8. Despite this advance, exactly how position and polarity cues translate into differences in Hippo pathway activity remained unclear. Adding to this disparate body of knowledge, accumulating evidence9,10 indicated that a cell's position depends on its contractility. Maitre and colleagues' study1 combines theory and experiment to unify the existing models of ICM–trophectoderm fate choice, and also provides a mechanistic link between cell polarity, position and Hippo pathway activity (Fig. 1).
The authors showed that asymmetric segregation of a polarized apical domain at cell division generates two daughter blastomeres with differential levels of contractility. Daughter cells that receive the apical domain are less contractile than their apolar sisters. The researchers then found that apolar blastomeres have higher levels of the scaffolding protein actomyosin than their polarized counterparts, directly translating into increased contractility. These differences in contractility trigger the sorting of cells to internal or external positions, because the less-contractile polarized cells have a tendency to spread over the apolar cells, which become internalized.
Support for this model came from a series of experiments in which Maitre et al. measured the surface tension of individual blastomeres, and then traced those cells over time in embryos to determine which lineage they adopted. This involved the development of technically sophisticated methods to probe the mechanics of individual cells and then track cells in embryos. Furthermore, the authors found that altering a cell's contractility altered its fate.
Finally, they demonstrated that contractility controls the subcellular position of the transcriptional co-activator protein Yap, a central component of the Hippo pathway. In less-contractile, polarized cells, Yap translocated to the nucleus, leading to activation of trophectoderm-specific genes. In apolar, highly contractile cells, Yap remained excluded from the nucleus. Linking Yap activity to differences in cell contractility connects the mechanical properties of blastomeres to their cell-fate choices, suggesting that mechanosensing may affect early lineage decisions.
Mammalian embryos are renowned for their ability to develop normally following alterations in internal architecture, or the loss or addition of cells. It has been proposed11 that activation of dormant mechanisms might help embryos to successfully carry out development following perturbations. Indeed, Maitre et al. showed that the mechanism responsible for ICM or trophectoderm specification is also probably used to compensate for perturbations, and thus underpins the regulative nature of mammalian embryos. By mixing cells with differential contractility, the authors demonstrated that those with elevated contractility adopted an internal position within embryos, whereas those with reduced contractility adopted an outside position. A mechanistic link between the position of a cell, its contractility and its gene-expression profile explains how the cell might 'sense' and consequently 'adjust' its position in the embryo, altering gene expression accordingly.
Although the current study represents a major breakthrough in our understanding of early mammalian development, several questions remain open. For instance, it is still not clear what triggers the initial blastomere polarization and differential contractility. It has been shown that modulating key transcription factors that control cell fate can influence cell position within an embryo, and so a feedback mechanism perhaps translates changes in gene expression into changes in contractility. In addition, the mechanism by which actomyosin affects the subcellular positioning of Yap needs to be determined.
Perhaps most important is that the results of Maitre and colleagues' study beg the question of whether the same mechanism is used in a variety of developmental contexts. Is mechanosensing through cellular contractility repeatedly used to regulate a cell's propensity to adopt alternative fates? The answer is sure to provide valuable insights into how lineage decisions are made in the mammalian embryo.Footnote 1
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Plusa, B., Hadjantonakis, AK. Mechanics drives cell differentiation. Nature 536, 281–282 (2016). https://doi.org/10.1038/nature18920
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