Controlling periodic long-range signalling to drive a morphogenetic transition.

Cells use signal relay to transmit information across tissue scales. However, the production of information carried by signal relay remains poorly characterised. To determine how the coding features of signal relay are generated, we used the classic system for long-range signalling: the periodic cAMP waves that drive Dictyostelium collective migration. Combining imaging and optogenetic perturbation of cell signalling states, we find that migration is triggered by an increase in wave frequency generated at the signalling centre. Wave frequency is regulated by cAMP wave circulation, which organises the long-range signal. To determine the mechanisms modulating wave circulation, we combined mathematical modelling, the general theory of excitable media, and mechanical perturbations to test competing models. Models in which cell density and spatial patterning modulate the wave frequency cannot explain the temporal evolution of signalling waves. Instead, our evidence leads to a model where wave circulation increases the ability for cells to relay the signal, causing further increase in the circulation rate. This positive feedback between cell state and signalling pattern regulates the long-range signal coding that drives morphogenesis.