Robust coordination of collective oscillatory signaling requires single-cell excitability and fold-change detection

Abstract

Complex multicellular behaviors are coordinated at the level of biochemical signaling networks, yet how this decentralized mechanism enables robust control in variable environments and over many orders of magnitude of spatiotemporal scales remains an open question. A stunning example of these behaviors is found in the microbe Dictyostelium discoideum, which uses the small molecule cyclic AMP (cAMP) to drive the propagation of collective signaling oscillations leading to multicellular development. The critical design features of the Dictyostelium signaling network remain unclear despite decades of mathematical modeling and experimental interrogation because each model makes different assumptions about the network architecture and in general, normalizing models for direct comparison presents a major challenge. We overcome this challenge by using recent experimental data to normalize the time and response scales of five major signal relay network models to one another and assess their ability to recapitulate experimentally-observed population and single-cell dynamics. We find that to successfully reproduce the full range of observed dynamical behaviors, single cells must be excitable and respond to the relative fold-change of environmental signals. This suggests these features represent robust principles for coordinating cellular populations through oscillatory signaling and that single-cell excitable dynamics are a generalizable route for controlling population behaviors.