Chemotaxis in shallow gradients is mediated independently of PtdIns 3-kinase by biased choices between random protrusions

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Current models of eukaryotic chemotaxis propose that directional sensing causes localized generation of new pseudopods1. However, quantitative analysis of pseudopod generation suggests a fundamentally different mechanism for chemotaxis in shallow gradients: first, pseudopods in multiple cell types are usually generated when existing ones bifurcate and are rarely made de novo; second, in Dictyostelium cells in shallow chemoattractant gradients, pseudopods are made at the same rate whether cells are moving up or down gradients. The location and direction of new pseudopods are random within the range allowed by bifurcation and are not oriented by chemoattractants. Thus, pseudopod generation is controlled independently of chemotactic signalling. Third, directional sensing is mediated by maintaining the most accurate existing pseudopod, rather than through the generation of new ones. Finally, the phosphatidylinositol 3-kinase (PI(3)K) inhibitor LY294002 affects the frequency of pseudopod generation, but not the accuracy of selection, suggesting that PI(3)K regulates the underlying mechanism of cell movement, rather than control of direction.

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Figure 1: Cells of different types generate new protrusions by subdividing existing ones.
Figure 2: Rate of pseudopod production does not depend on orientation.
Figure 3: Probability of survival of a pseudopod is biased by its position in a gradient.
Figure 4: Cells chemotax by generating many pseudopods and retaining the better ones.
Figure 5: Blocking PI(3)K alters the dynamics of pseudopod generation, but not the directional accuracy of the cell.


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Thanks to S. Dimmock and T. Luu for help with isolating human neutrophils. Thanks to J. A. Legg for preparing fibroblast cultures.

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N.A. performed all published experiments and numerial analysis. R.I. performed prelininary experiments. N.A. and R.I. planned the work and wrote the paper together.

Correspondence to Robert H Insall.

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