Abstract
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 ~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.
Highlights
How spatial and temporal information are integrated to determine the direction of cell migration remains poorly understood
Aggregation of Dictyostelium discoideum appears to have partly solved this problem by selfenhancing cell-to-cell relay of chemoattractant cyclic AMP in the form of non-dissipating waves
The two protein kinase B isoforms in Dictyostelium are regulated by target of rapamycin complex 2 (TORC2) and PI3K17,20,21, and their null-mutants are heavily impaired in their chemotactic ability[22]
Summary
How spatial and temporal information are integrated to determine the direction of cell migration remains poorly understood. 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. Because gradient reverses during the wave passage, it remains unclear how cells avoid futile back-and-forth movement[9,10,11] This is the so-called ‘back-of-the-wave’ problem in Dictyostelium cell aggregation. Synthesis[28], chemotactic cell movement[29] as well as tracking of isolated cells in the vicinity of aggregating streams[30] showed no evidence for refractoriness in directional sensing
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