Rectified directional sensing in long-range cell migration

How spatial and temporal information are integrated to determine the direction of cell migration remains poorly understood. Here, by precise microfluidics emulation of dynamic chemoattractant waves, we demonstrate that, in Dictyostelium, directional movement as well as activation of small guanosine triphosphatase Ras at the leading edge is suppressed when the chemoattractant concentration is decreasing over time. This 'rectification' of directional sensing occurs only at an intermediate range of wave speed and does not require phosphoinositide-3-kinase or F-actin. From modelling analysis, we show that rectification arises naturally in a single-layered incoherent feedforward circuit with zero-order ultrasensitivity. The required stimulus time-window predicts similar to 5 s transient for directional sensing response close to Ras activation and inhibitor diffusion typical for protein in the cytosol. We suggest that the ability of Dictyostelium cells to move only in the wavefront is closely associated with rectification of adaptive response combined with local activation and global inhibition.