A structural basis of cell fate precision

Developing systems show an unmatched complexity due to a highly entangled regulation across different levels of organization. Accordingly, certain cell functions occur in response to cues spanning biological scales. Can cells learn to perform certain functions in response to global cues propagated in the tissue they are embedded in? We address this top-down regulation of cell functions by using a physics-guided quantitative developmental biology approach combined with tailored in vivo engineering. Here we show that the first cell fate decisions in zebrafish, the specification of the meso-endodermal germ layer, relies on a mechanochemical feedback between morphogen signalling and the collective tissue material state. Using live imaging and statistical mechanics, we observe that when cells start receiving specification signals the tissue is operating close to a critical point of a rigidity phase transition. Once cells change their fate, they switch-off the specification signals, and the tissue transitions to a rigid regime. By using genetics to block cell fate specification, we observe that the tissue stays at criticality, suggesting that tissue rigidification occurs downstream of biochemical morphogen signalling. Remarkably, when we opto-genetically interfere with tissue rigidification and prolong the duration of the system at criticality, cells keep specifying and do not switch-off specification signals. By found that morphogen gradient formation is impacted by the tissue material state, where at criticality morphogens diffuse further and faster in the tissue, whereas during rigidification their diffusion is hampered. This suggests that a self-generated mechanism of morphogen gradient formation transcending biological scales patterns the vertebrate embryo, and proposes that cells use the tissue material state as a form of physical learning to achieve a certain functionality, in this case, the exit from pluripotency.