In the LEGI model, receptor activation initiates a rapid and localized activating signal, followed by a slower global inhibitory signal to account for symmetry breaking and acquisition of polarized migratory morphology and, ultimately, directional migration. Xiong and colleagues recently proposed that motile cells navigate with a LEGI-biased excitable network, using simulations based on a model that accounts for the two transient waves of signaling events and excitability of the biochemical network that is activated within the first five minutes of chemoattractant stimulation of migrating cells. These simulations can predict cellular responses under directional chemoattractant stimulatory conditions where the parameters of the LEGI-biased excitable network model can be altered to mimic known motility defects. For example, by lowering the excitability of the network parameter, such as decreasing the threshold of a positive feedback loop, this LEGI-model predicted that the spontaneous activity of the system would be eliminated but directional sensing would be maintained. Furthermore, Xiong and colleagues drew attention to how this perturbance in the excitable network is reminiscent of cells treated with Latrunculin A, which prevents actin polymerization, similar to WASp-deficiency. Indeed, Dictyostelium cells with reduced WASp expression have reduced F-actin levels following cAMP stimulation, and fewer and mislocalized barbed ends, indicative of the role of WASp in actin polymerization during chemotaxis. However, whereas F-actin could not distribute towards the direction of the cAMP gradient, Akt was able to localize correctly to the plasma membrane, indicating that the pathways regulating PIP33 levels remained intact. Our results are consistent with the LEGIbiased excitable model since WASp-deficient macrophages respond to directional CSF-1 stimulation but the protrusions were not maintained. The role of phosphorylation of tyrosine residue 291 of WASp has been studied in detail in vitro. While the phosphodeficient WASp showed comparable rates of actin polymerization in vitro, our in vivo characterization revealed that actin polymerization by Y291F cells in response to CSF-1 was identical to shWASp cells, consistent with the inability of Y291F WASp expressing cells to migrate towards CSF-1. Interestingly, Y291F showed an even greater defect in the initiation of the chemotactic response compared to shWASp cells in the micropipette assay, suggesting that tyrosine phosphorylation of WASp does not appear to simply regulate the efficiency of actin polymerization. Instead, the difference in the cellular responses of Y291F cells to control cells during upshift and directional CSF-1 stimulations may be due to mistargeting of WASp during chemotactic responses, since WASp phosphorylation has been suggested to play a role in the subcellular localization of active WASp in macrophages. Taken together, these results suggest that localization of WASp by tyrosine phosphorylation may be required to restrict actin polymerization towards the chemoattractant, consistent, at least in part, with the LEGI model. Alternatively, WASp may play a role in adhesion of chemotactic protrusions leading to their maintenance since protrusions will often retract if not BAY-60-7550 stabilized by substrate adhesion even in the continued presence of a chemoattractant gradient, as reported in Dictyostelium amoebae, carcinoma cells and neutrophils.