Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Nature Cell Biology volume 9, pages 193–200 (2007)Cite this article

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Firtel, R. A. & Chung, C. Y. The molecular genetics of chemotaxis: sensing and responding to chemoattractant gradients. Bioessays 22, 603–615 (2000).

    Article  CAS  Google Scholar 

  2. Devreotes, P. N. & Zigmond, S. H. Chemotaxis in eukaryotic cells: a focus on leukocytes and Dictyostelium. Annu. Rev. Cell Biol. 4, 649–686 (1988).

    Article  CAS  Google Scholar 

  3. Zigmond, S. H. Ability of polymorphonuclear leukocytes to orient in gradients of chemotactic factors. J. Cell Biol. 75, 606–616 (1977).

    Article  CAS  Google Scholar 

  4. Parent, C. A., Blacklock, B. J., Froehlich, W. M., Murphy, D. B. & Devreotes, P. N. G-protein signaling events are activated at the leading edge of chemotactic cells. Cell 95, 81–91 (1998).

    Article  CAS  Google Scholar 

  5. Devreotes, P. & Janetopoulos, C. Eukaryotic chemotaxis: distinctions between directional sensing and polarization. J. Biol. Chem. 278, 20445–20448 (2003).

    Article  CAS  Google Scholar 

  6. Sun, C. X. et al. Rac1 is the small GTPase responsible for regulating the neutrophil chemotaxis compass. Blood 104, 3758–3765 (2004).

    Article  CAS  Google Scholar 

  7. Weiner, O. D. Regulation of cell polarity during eukaryotic chemotaxis: the chemotactic compass. Curr. Opin. Cell Biol. 14, 196–202 (2002).

    Article  CAS  Google Scholar 

  8. Gerisch, G. & Keller, H. U. Chemotactic reorientation of granulocytes stimulated with micropipettes containing fMet-Leu-Phe. J. Cell Sci. 52, 1–10 (1981).

    CAS  PubMed  Google Scholar 

  9. Wessels, D., Murray, J., Jung, G., Hammer, J. A. & Soll, D. R. Myosin IB null mutants of Dictyostelium exhibit abnormalities in motility. Cell Motil. Cytoskeleton 20, 301–315 (1991).

    Article  CAS  Google Scholar 

  10. Wessels, D. et al. RasC plays a role in transduction of temporal gradient information in the cyclic-AMP wave of Dictyostelium discoideum. Eukaryot. Cell 3, 646–662 (2004).

    Article  CAS  Google Scholar 

  11. Chen, L. et al. Two phases of actin polymerization display different dependencies on PI(3,4,5)P3 accumulation and have unique roles during chemotaxis. Mol. Biol. Cell 14, 5028–5037 (2003).

    Article  CAS  Google Scholar 

  12. Ma, L., Janetopoulos, C., Yang, L., Devreotes, P. N. & Iglesias, P. A. Two complementary, local excitation, global inhibition mechanisms acting in parallel can explain the chemoattractant-induced regulation of PI(3,4,5)P3 response in Dictyostelium cells. Biophys. J. 87, 3764–3774 (2004).

    Article  CAS  Google Scholar 

  13. Brahmbhatt, A. A. & Klemke, R. L. ERK and RhoA differentially regulate pseudopodia growth and retraction during chemotaxis. J. Biol. Chem. 278, 13016–13025 (2003).

    Article  CAS  Google Scholar 

  14. Shutt, D. C. et al. Ponticulin plays a role in the positional stabilization of pseudopods. J. Cell Biol. 131, 1495–1506 (1995).

    Article  CAS  Google Scholar 

  15. Stepanovic, V., Wessels, D., Daniels, K., Loomis, W. F. & Soll, D. R. Intracellular role of adenylyl cyclase in regulation of lateral pseudopod formation during Dictyostelium chemotaxis. Eukaryot. Cell 4, 775–786 (2005).

    Article  CAS  Google Scholar 

  16. Wang, Y. & O'Halloran, T. J. Abp1 regulates pseudopodium number in chemotaxing Dictyostelium cells. J. Cell Sci. 119, 702–710 (2006).

    Article  CAS  Google Scholar 

  17. Wessels, D., Titus, M. & Soll, D. R. A Dictyostelium myosin I plays a crucial role in regulating the frequency of pseudopods formed on the substratum. Cell Motil. Cytoskeleton 33, 64–79 (1996).

    Article  CAS  Google Scholar 

  18. Carlier, M. F., Wiesner, S., Le Clainche, C. & Pantaloni, D. Actin-based motility as a self-organized system: mechanism and reconstitution in vitro. C. R. Biol 326, 161–170 (2003).

    Article  CAS  Google Scholar 

  19. Arrieumerlou, C. & Meyer, T. A local coupling model and compass parameter for eukaryotic chemotaxis. Dev. Cell 8, 215–227 (2005).

    Article  CAS  Google Scholar 

  20. Tranquillo, R. T., Lauffenburger, D. A. & Zigmond, S. H. A stochastic model for leukocyte random motility and chemotaxis based on receptor binding fluctuations. J. Cell Biol. 106, 303–309 (1988).

    Article  CAS  Google Scholar 

  21. Bourne, H. R. & Weiner, O. A chemical compass. Nature 419, 21 (2002).

    Article  CAS  Google Scholar 

  22. Zigmond, S. H., Levitsky, H. I. & Kreel, B. J. Cell polarity: an examination of its behavioral expression and its consequences for polymorphonuclear leukocyte chemotaxis. J. Cell Biol. 89, 585–592 (1981).

    Article  CAS  Google Scholar 

  23. Swanson, J. A. & Taylor, D. L. Local and spatially coordinated movements in Dictyostelium discoideum amoebae during chemotaxis. Cell 28, 225–232 (1982).

    Article  CAS  Google Scholar 

  24. Blagg, S. L., Stewart, M., Sambles, C. & Insall, R. H. PIR121 regulates pseudopod dynamics and SCAR activity in Dictyostelium. Curr. Biol. 13, 1480–1487 (2003).

    Article  CAS  Google Scholar 

  25. Postma, M. et al. Uniform cAMP stimulation of Dictyostelium cells induces localized patches of signal transduction and pseudopodia. Mol. Biol. Cell 14, 5019–5027 (2003).

    Article  CAS  Google Scholar 

  26. Postma, M. et al. Sensitization of Dictyostelium chemotaxis by phosphoinositide-3-kinase-mediated self-organizing signalling patches. J. Cell Sci. 117, 2925–2935 (2004).

    Article  CAS  Google Scholar 

  27. Meinhardt, H. Orientation of chemotactic cells and growth cones: models and mechanisms. J. Cell Sci. 112, 2867–2874 (1999).

    CAS  PubMed  Google Scholar 

  28. Postma, M. & Van Haastert, P. J. A diffusion-translocation model for gradient sensing by chemotactic cells. Biophys. J. 81, 1314–1323 (2001).

    Article  CAS  Google Scholar 

  29. Sheikh, S. & Nash, G. B. Continuous activation and deactivation of integrin CD11b/CD18 during de novo expression enables rolling neutrophils to immobilize on platelets. Blood 87, 5040–5050 (1996).

    CAS  PubMed  Google Scholar 

  30. Laevsky, G. & Knecht, D. A. Under-agarose folate chemotaxis of Dictyostelium discoideum amoebae in permissive and mechanically inhibited conditions. Biotechniques 31, 1140–1149 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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

Author information

Authors and Affiliations

  1. School of Biosciences, The University of Birmingham, Edgbaston, B15 2TT, Birmingham, UK

    Natalie Andrew & Robert H Insall

Authors
  1. Natalie Andrew
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert H Insall
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Robert H Insall.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Figures S1, S2, S3 and S4 (PDF 1571 kb)

Supplementary Information

Supplementary Movie S1 (MOV 1167 kb)

Supplementary Information

Supplementary Movie S2 (MOV 840 kb)

Supplementary Information

Supplementary Movie S3 (MOV 729 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Andrew, N., Insall, R. Chemotaxis in shallow gradients is mediated independently of PtdIns 3-kinase by biased choices between random protrusions. Nat Cell Biol 9, 193–200 (2007). https://doi.org/10.1038/ncb1536

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1536

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing