Molecular Neurobiology

, Volume 21, Issue 1–2, pp 97–107

Signal-regulated ADF/cofilin activity and growth cone motility

  • Peter J. Meberg


It is becoming increasingly evident that proteins of the actin depolymerizing factor (ADF)/cofilin family are essential regulators of actin turnover required for many actin-based cellular processes, including motility. ADF can increase actin turnover by either increasing the rate of actin filament treadmilling or by severing actin filaments. In neurons ADF is highly expressed in neuronal growth cones and its activity is regulated by many signals that affect growth cone motility. In addition, increased activity of ADF causes an increase in neurite extension. ADF activity is inhibited upon phosphorylation by LIM kinases (LIMK), kinases activated by members of the Rho family of small GTPases. ADF become dephosphorylated downstream of signal pathways that activate PI-3 kinase or increase levels of intracellular calcium. The growth-regulating effects of ADF together with its ability to be regulated by a wide variety of guidance cues, suggest that ADF may regulate growth cone advance and navigation.

Index Entries

Actin depolymerizing factor cofilin growth cone actin filaments phosphorylation LIM kinase Rho family GTPases 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Nobes C. D. and Hall A. (1995) Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 81, 53–62.PubMedCrossRefGoogle Scholar
  2. 2.
    Luo L., Liao Y. J., Jan L. Y., and Jan Y. N. (1994) Distinct morphogenetic functions of similar small GTPases: Drosophila Drac1 is involved in axonal outgrowth and myoblast fusion. Genes Dev. 8, 1787–1802.PubMedCrossRefGoogle Scholar
  3. 3.
    Jin Z. and Strittmatter S. M. (1997) Rac1 mediates collapsin-1-induced growth cone collapse. J. Neurosci. 17, 6256–6263.PubMedGoogle Scholar
  4. 4.
    Kuhn T. B., Brown M. D., and Bamburg J. R. (1998) Rac1-dependent actin filament organization in growth cones is necessary for beta1-integrin-mediated advance but not for growth on poly-D-lysine. J. Neurobiol. 37, 524–540.PubMedCrossRefGoogle Scholar
  5. 5.
    Kuhn T. B., Brown M. D., Wilcox C. L., Raper J. A., and Bamburg J. R. (1999) Myelin and collapsin-1 induce motor neuron growth cone collapse through different pathways: inhibition of collapse by opposing mutants of rac1. J. Neurosci. 19, 1965–1975.PubMedGoogle Scholar
  6. 6.
    Brown M. D., Cornejo B. J., Kuhn T. B., and Bamburg J. R. (2000) Cdc42 stimulates neurite outgrowth and formation of growth cone filopodia and lamellipodia. J. Neurobiol. 43, 352–364.PubMedCrossRefGoogle Scholar
  7. 7.
    Song H. J. and Poo M. M. (1999) Signal transduction underlying growth cone guidance by diffusible factors. Curr. Opin. Neurobiol. 9, 355–363.PubMedCrossRefGoogle Scholar
  8. 8.
    Bamburg J. R. (1999) Proteins of the ADF/cofilin family: essential regulators of actin dynamics. Annu. Rev. Cell Dev. Biol. 15, 185–230.PubMedCrossRefGoogle Scholar
  9. 9.
    Carlier M. F., Ressad F., and Pantaloni D. (1999) Control of actin dynamics in cell motility. Role of ADF/cofilin. J. Biol. Chem. 274, 33,827–33,830.CrossRefGoogle Scholar
  10. 10.
    Chen H., Bernstein B. W., and Bamburg J. R. (2000) Regulating actin-filament dynamics in vivo. Trends Biochem. Sci. 25, 19–23.PubMedCrossRefGoogle Scholar
  11. 11.
    Mitchison T. J. and Cramer L. P. (1996) Actin-based cell motility and cell locomotion. Cell 84, 371–379.PubMedCrossRefGoogle Scholar
  12. 12.
    Lewis A. K. and Bridgman P. C. (1992) Nerve growth cone lamellipodia contain two populations of actin filaments that differ in organization and polarity. J. Cell Biol. 119, 1219–1243.PubMedCrossRefGoogle Scholar
  13. 13.
    Smith S. J. (1988) Neuronal cytomechanics: the actin-based motility of growth cones. Science 242, 708–715.PubMedCrossRefGoogle Scholar
  14. 14.
    Lin C.-H. and Forscher P. (1995) Growth cone advance is inversely proportional to retrograde F-actin flow. Neuron 14, 763–771.PubMedCrossRefGoogle Scholar
  15. 15.
    Forscher P. and Smith S. J. (1988) Actions of cytochalasins on the organization of actin filaments and microtubules in a neuronal growth cone. J. Cell Biol. 107, 1505–1516.PubMedCrossRefGoogle Scholar
  16. 16.
    Bentley D. and Toroian-Raymond A. (1986) Disoriented pathfinding by pioneer neurone growth cones deprived of filopodia by cytochalasin treatment. Nature 323, 712–715.PubMedCrossRefGoogle Scholar
  17. 17.
    Lin C.-H. and Forscher P. (1993) Cytoskeletal remodeling during growth cone-target interactions. J. Cell Biol. 121, 1369–1383.PubMedCrossRefGoogle Scholar
  18. 18.
    O’Connor T. P. and Bentley D. (1993) Accumulation of actin in subsets of pioneer growth cone filopodia in response to neural and epithelial guidance cues in situ. J. Cell Biol. 123, 935–948.PubMedCrossRefGoogle Scholar
  19. 19.
    Fan J., Mansfield S. G., Redmond T., Gordon-Weeks P. R., and Raper J. A. (1993) The organization of F-actin and microtubules in growth cones exposed to a brain-derived collapsing factor. J. Cell Biol. 121, 867–878.PubMedCrossRefGoogle Scholar
  20. 20.
    Fritsche J., Reber B. F., Schindelholz B., and Bandtlow C. E. (1999) Differential cytoskeletal changes during growth cone collapse in response to hSema III and thrombin. Mol. Cell Neurosci. 14, 398–418.PubMedCrossRefGoogle Scholar
  21. 21.
    Theriot J. A. and Mitchison T. J. (1991) Actin microfilament dynamics in locomoting cells. Nature 352, 126–131.PubMedCrossRefGoogle Scholar
  22. 22.
    Borisy G. G. and Svitkina T. M. (2000) Actin machinery: pushing the envelope. Curr. Opin. Cell Biol. 12, 104–112.PubMedCrossRefGoogle Scholar
  23. 23.
    Suter D. M. and Forscher P. (1998) An emerging link between cytoskeletal dynamics and cell adhesion molecules in growth cone guidance. Curr. Opin. Neurobiol. 8, 106–116.PubMedCrossRefGoogle Scholar
  24. 24.
    Goldberg D. J., Foley M. S., Tang D., and Grabham P. W. (2000) Recruitment of the Arp2/3 complex and mena for the stimulation of actin polymerization in growth cones by nerve growth factor. J. Neurosci. Res. 60, 458–467.PubMedCrossRefGoogle Scholar
  25. 25.
    Loisel T. P., Boujemaa R., Pantaloni D., and Carlier M. F. (1999) Reconstitution of actin-based motility of Listeria and Shigella using pure proteins. Nature 401, 613–616.PubMedCrossRefGoogle Scholar
  26. 26.
    Lanier L. M., Gates M. A., Witke W., Menzies A. S., Wehman A. M., Macklis J. D., et al. (1999) Mena is required for neurulation and commissure formation. Neuron 22, 313–325.PubMedCrossRefGoogle Scholar
  27. 27.
    Wills Z., Marr L., Zinn K., Goodman C. S., and Van Vactor D. (1999) Profilin and the Abl tyrosine kinase are required for motor axon outgrowth in the Drosophila embryo. Neuron 22, 291–299.PubMedCrossRefGoogle Scholar
  28. 28.
    Banzai Y., Miki H., Yamaguchi H., and Takenawa T. (2000) Essential role of neural Wiskott-Aldrich syndrome protein in neurite extension in PC12 cells and rat hippocampal primary culture cells. J. Biol. Chem. 275, 11,987–11,992.CrossRefGoogle Scholar
  29. 29.
    Sobue K. and Kanda K. (1989) Alpha-actinins, calspectin (brain spectrin or fodrin), and actin participate in adhesion and movement of growth cones. Neuron 3, 311–319.PubMedCrossRefGoogle Scholar
  30. 30.
    Bamburg J. R., McGough A., and Ono S. (1999) Putting a new twist on actin: ADF/cofilins modulate actin dynamics. Trends Cell Biol. 9, 364–370.PubMedCrossRefGoogle Scholar
  31. 31.
    Iida K., Moriyama K., Matsumoto S., Kawasaki H., Nishida E., and Yahara I. (1993) Isolation of a yeast essential gene, COF1, that encodes a homologue of mammalian cofilin, a low-M(r) actin-binding and depolymerizing protein. Gene 124, 115–120.PubMedCrossRefGoogle Scholar
  32. 32.
    Devineni N., Minamide L. S., Niu M., Safer D., Verma R., Bamburg J. R., and Nachmias V. T. (1999) A quantitative analysis of G-actin binding proteins and the G-actin pool in developing chick brain. Brain Res. 823, 129–140.PubMedCrossRefGoogle Scholar
  33. 33.
    Meberg P. J., Ono S., Minamide L. S., Takahashi M., and Bamburg J. R. (1998) Actin depolymerizing factor and cofilin phosphorylation dynamics: response to signals that regulate neurite extension. Cell. Motil. Cytoskeleton. 39, 172–190.PubMedCrossRefGoogle Scholar
  34. 34.
    Svitkina T. M. and Borisy G. G. (1999) Arp2/3 complex and ADF/cofilin in dendritic organization and treadmilling of actin filament array in lamellipodia. J. Cell Biol. 145, 1009–1026.PubMedCrossRefGoogle Scholar
  35. 35.
    Chan A. Y., Bailly M., Zebda N., Segall J. E., and Condeelis J. S. (2000) Role of cofilin in epidermal growth factor-stimulated actin polymerization and lamellipod protrusion. J. Cell Biol. 148, 531–542.PubMedCrossRefGoogle Scholar
  36. 36.
    Bamburg J. R. and Bray D. (1987) Distribution and cellular localization of actin depolymerizing factor. J. Cell Biol. 105, 2817–2825.PubMedCrossRefGoogle Scholar
  37. 37.
    Minamide L. S., Streigl A. M., Boyle J. A., Meberg P. J., and Bamburg J. R. (2000) Neurodegenerative stimuli induce persistent ADF/cofilin-actin rods that disrupt distal neurite function. Nature Cell Biol. 2, 628–636.PubMedCrossRefGoogle Scholar
  38. 38.
    Moriyama K. and Yahara I. (1999) Two activities of cofilin, severing and accelerating directional depolymerization of actin filaments, are affected differentially by mutations around the actin-binding helix. EMBO J. 18, 6752–6761.PubMedCrossRefGoogle Scholar
  39. 39.
    Morgan T. E., Lockerbie R. O., Minamide L. S., Browning M. D., and Bamburg J. R. (1993) Isolation and characterization of a regulated form of actin depolymerizing factor. J. Cell Biol. 122, 623–633.PubMedCrossRefGoogle Scholar
  40. 40.
    Agnew B. J., Minamide L. S., and Bamburg J. R. (1995) Reactivation of phosphorylated actin depolymerizing factor and identification of the regulatory site. J. Biol. Chem. 270, 17,582–17,587.Google Scholar
  41. 41.
    Abe H., Obinata T., Minamide L. S., and Bamburg J. R. (1996) Xenopus laevis actin-depolymerizing factor/cofilin: a phosphorylation-regulated protein essential for development. J. Cell Biol. 132, 871–885.PubMedCrossRefGoogle Scholar
  42. 42.
    Abe H., Verrastro T. A., Brown M. D., Minanide L. S., Caddoo W. S., Agnew B. J., et al. (1995) Xenopus development is dependent on upon the regulation of ADF/cofilin by phosphorylation. Mol. Biol. Cell Suppl. 6, 22a.Google Scholar
  43. 43.
    Moon A. and Drubin D. G. (1995) The ADF/cofilin proteins: stimulus-responsive modulators of actin dynamics. Mol. Biol. Cell 6, 1423–1431.PubMedGoogle Scholar
  44. 44.
    Arber S., Barbayannis F. A., Hanser H., Schneider C., Stanyon C. A., Bernard O., and Caroni P. (1998) Regulation of actin dynamics through phosphorylation of cofilin by LIM- kinase. Nature 393, 805–809.PubMedCrossRefGoogle Scholar
  45. 45.
    Yang N., Niguchi O., Ohashi K., Nagata K., Wada A., Kangawa K., Nishida E., and Mizuno K. (1998) Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization. Nature 393, 809–812.PubMedCrossRefGoogle Scholar
  46. 46.
    Frangiskakis J. M., Ewart A. K., Morris C. A., Mervis C. B., Bertrand J., Robinson B. F., et al. (1996) LIM-kinase1 hemizygosity implicated in impaired visuospatial constructive cognition. Cell 86, 59–69.PubMedCrossRefGoogle Scholar
  47. 47.
    Tassabehji M., Metcalfe K., Karmiloff-Smith A., Carette M. J., Grant J., Dennis N., et al. (1999) Williams syndrome: use of chromosomal microdeletions as a tool to dissect cognitive and physical phenotypes. Am. J. Hum. Genet. 64, 118–125.PubMedCrossRefGoogle Scholar
  48. 48.
    Edwards D. C., Sanders L. C., Bokoch G. M., and Gill G. N. (1999) Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics. Nature Cell Biol. 1, 253–259.PubMedCrossRefGoogle Scholar
  49. 49.
    Maekawa M., Ishizaki T., Boku S., Watanabe N., Fujita A., Iwamatsu A., et al. (1999) Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science 285, 895–898.PubMedCrossRefGoogle Scholar
  50. 50.
    Sumi T., Matsumoto K., Takai Y., and Nakamura T. (1999) Cofilin phosphorylation and actin cytoskeletal dynamics regulated by rho- and Cdc42-activated LIM-kinase 2. J. Cell Biol. 147, 1519–1532.PubMedCrossRefGoogle Scholar
  51. 51.
    Ohashi K., Nagata K., Maekawa M., Ishizaki T., Narumiya S., and Mizuno K. (2000) Rho-associated kinase ROCK activates LIM-kinase 1 by phosphorylation at threonine 508 within the activation loop. J. Biol. Chem. 275, 3577–3582.PubMedCrossRefGoogle Scholar
  52. 52.
    Luo L., Jan L., and Jan Y. N. (1996) Small GTPases in axon outgrowth. Perspect. Dev. Neurobiol. 4, 199–204.PubMedGoogle Scholar
  53. 53.
    Jackson T. R., Blader I. J., Hammonds-Odie L. P., Burga C. R., Cooke F., Hawkins P. T., et al. (1996) Initiation and maintenance of NGF-stimulated neurite outgrowth requires activation of a phosphoinositide 3-kinase. J. Cell Sci. 109, 289–300.PubMedGoogle Scholar
  54. 54.
    Rodriguez-Viciana P., Warne P. H., Khwaja A., Marte B. M., Pappin D., Das P., et al. (1997) Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell 89, 457–467.PubMedCrossRefGoogle Scholar
  55. 55.
    Jalink K., van Corven E. J., Hengeveld T., Morii N., Narumiya S., and Moolenaar W. H. (1994) Inhibition of lysophosphatidate-and thrombin-induced neurite retraction and neuronal cell rounding by ADP ribosylation of the small GTP-binding protein Rho. J. Cell Biol. 126, 801–810.PubMedCrossRefGoogle Scholar
  56. 56.
    Tigyi G., Fischer D. J., Sebok A., Marshall F., Dyer D. L., and Miledi R. (1996) Lysophosphatidic acid-induced neurite retraction in PC12 cells: neurite- protective effects of cyclic AMP signaling. J. Neurochem. 66, 549–158.PubMedCrossRefGoogle Scholar
  57. 57.
    Brown M. D. and Bamburg J. R. (1997) Regulation of the phosphorylation of Xenopus ADF/cofilin during cytokinesis by Rac1. Mol. Biol. Cell Suppl. 8, 366a.Google Scholar
  58. 58.
    Ridley A. J., Paterson H. F., Johnston C. L., Diekmann D., and Hall A. (1992) The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell 70, 401–410.PubMedCrossRefGoogle Scholar
  59. 59.
    Peppelenbosch M. P., Qiu R. G., de Vries-Smits A. M., Tertoolen L. G., de Laat S. W., McCormick F., et al. (1995) Rac mediates growth factor-induced arachidonic acid release. Cell 81, 849–856.PubMedCrossRefGoogle Scholar
  60. 60.
    Meberg P. J. and Bamburg J. R. (2000) Increase in neurite outgrowth mediated by overexpression of actin depolymerizing factor. J. Neurosci. 20, 2459–2469.PubMedGoogle Scholar
  61. 61.
    Welnhofer E. A., Zhao L., and Cohan C. S. (1999) Calcium influx alters actin bundle dynamics and retrograde flow in Helisoma growth cones. J. Neurosci. 19, 7971–7982.PubMedGoogle Scholar
  62. 62.
    Mallavarapu A. and Mitchison T. (1999) Regulated actin cytoskeleton assembly at filopodium tips controls their extension and retraction. J. Cell Biol. 146, 1097–1106.PubMedCrossRefGoogle Scholar
  63. 63.
    Bradke F. and Dotti C. G. (1999) The role of local actin instability in axon formation. Science 283, 1931–1934.PubMedCrossRefGoogle Scholar
  64. 64.
    Zheng J. Q., Felder M., Connor J. A., and Poo M. M. (1994) Turning of nerve growth cones induced by neurotransmitters. Nature 368, 140–144.PubMedCrossRefGoogle Scholar
  65. 65.
    Zheng J. Q., Wan J. J., and Poo M. M. (1996) Essential role of filopodia in chemotropic turning of nerve growth cone induced by a glutamate gradient. J. Neurosci. 16, 1140–1149.PubMedGoogle Scholar
  66. 66.
    Chang H. Y., Takei K., Sydor A. M., Born T., Rusnak F., and Jay D. G. (1995) Asymmetric retraction of growth cone filopodia following focal inactivation of calcineurin. Nature 376, 686–690.PubMedCrossRefGoogle Scholar
  67. 67.
    Lehmann M., Fournier A., Selles-Navarro I., Dergham P., Sebok A., Leclerc N., Tigyi G., and McKerracher L. (1999) Inactivation of Rho signaling pathway promotes CNS axon regeneration. J. Neurosci. 19, 7537–7547.PubMedGoogle Scholar
  68. 68.
    Wahl S., Barth H., Ciossek T., Aktories K., and Mueller B. K. (2000) Ephrin-A5 induces collapse of growth cones by activating Rho and Rho kinase. J. Cell Biol. 149, 263–270.PubMedCrossRefGoogle Scholar
  69. 69.
    McGough A., Pope B., Chiu W., and Weeds A. (1997) Cofilin changes the twist of F-actin: implications for actin filament dynamics and cellular function. J. Cell Biol. 138, 771–781.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2001

Authors and Affiliations

  • Peter J. Meberg
    • 1
  1. 1.Department of BiologyUniversity of North DakotaGrand Forks

Personalised recommendations