The game of fate: tracing the origin of heterogeneity and symmetry breaking in the early mammalian embryo

New paper on Nature Communications by Magda Zernicka Goetz in collaboration with researchers from the University of Nevada digs into one of the central questions of developmental biology, single cell differentiation

Abrstact: A fundamental question in developmental and stem cell biology concerns the origin and nature of signals that initiate asymmetry leading to pattern formation and self-organization. Instead of having prominent pre-patterning determinants as present in model organisms (worms, sea urchin, frog), we propose that the mammalian embryo takes advantage of more subtle cues such as compartmentalized intracellular reactions that generate micro-scale inhomogeneity, which is gradually amplified over several cellular generations to drive pattern formation while keeping developmental plasticity. It is therefore possible that by making use of compartmentalized information followed by its amplification, mammalian embryos would follow general principle of development found in other organisms in which the spatial cue is more robustly presented.

The regulatory vs. mosaic nature of cell fate specification process between embryos of mammals vs. other classic model metazoans (worms, sea
urchins, and frogs) tends to raise the intuitive idea that the embryonic cell fate decision process in classic model animals is deterministic, whereas in mammals it occurs at random.

As depicted here, in a pinball model of bifurcation of fates (see Figure), the inside trajectory of classic model metazoans could be as deterministic as
predesigned pinball tracks into fate A or B (see Figure, part a). However, does the plastic nature of embryonic cell fate in mammals mean that the
trajectory is completely random and unpredictable as an unregulated bouncing pinball (see Figure, part b). In fact, predictable factors could be
hardwired in a seemingly random system that inevitably bias the outcome. For example, when a “direction tube” (red) is embedded in the system, it
redirects the trajectory of a moving pinball from any direction toward a defined fate. This will systematically change the probability of ending up in one
fate (fate A) rather than another (fate B) (see Figure, part c).
When a more complicated system (which we call “The Game of Fate”) is embedded with multiple “direction tubes” with opposing effects (red vs. blue),
and additional layers of regulators such as a “quality control bar”, a “reversal bar”, and “irreversible tunnels” as depicted (see Figure, part d), the
system’s outcome in biasing the pinball’s fate would depend upon multiple factors such as the initial velocity, the angle of entrance, the number and
relative positions of hardwired elements, and thus the orders in which they are hit/triggered during the movements. Despite a certain degree of inherent
random behavior of the system, the triggering of defined regulatory elements can create a biased outcome. This Game could be to some extent
analogous to a mouse blastomere with undecided fate, where lineage specifiers with opposing effects co-exist inside the blastomere along with other regulatory factors (e.g., cell position and cell contact) and so blastomeres remain in an intermediate state before their fate is defined.