Coupling Mechanical Regulation with Biochemical Reaction-Diffusion Circuits Yields Robust Self-Organized Pattern Formation.

Cell-cell signaling circuits that combine local self-activation with long-range inhibition have long been proposed as a theoretical mechanism sufficient to generate cellular patterns, such as spots and stripes. Here we construct synthetic pattern-forming circuits, implementing local self-activation (positive feedback) using juxtacrine synNotch receptor interactions, and implementing long-range inhibition using diffusible competitor molecules. While combining local positive feedback with long-range inhibition leads to more spatially heterogeneous cell states, these synthetic circuits do not robustly lead to well defined patterns. We find, however, that if we couple these reaction-diffusion circuits with induction of genes that regulate cell mechanics - such Cadherin molecules that promote local cell adhesion and sorting - we observed the emergence of much more well-defined cellular patterns. Theoretical analysis indicates while reaction-diffusion circuits can be sufficient to generate patterns under precisely balanced parameter conditions, the close coupling of cell mechanical/sorting significantly increases the robustness of pattern formation (the parameter space yielding patterns). Thus, circuits that closely integrate signaling and mechanical changes may underlie many evolved morphogenic pattern formation systems.

Toda, S., Guan, G., Tambo, M., Morita, H., Lim, W. A.

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