What causes filopodia retraction and collapse?2018-02-06T10:34:59+00:00

What causes filopodia retraction and collapse?

Binding of filopodia to certain ligands or substratum may hinder filament assembly, thereby leading to changes that promote retraction, collapse or growth cone turning [1][2]. For example, substrate contacts with a repulsive signal on one side of a filopodium causes growth cone turning, while contact across the entire filopodial tip circumference causes complete filopodium collapse [1]. Normal retrograde flow of material continues under both circumstances and collapse is independent of the maintenance of growth cone protrusive activity [3]. Resorption and collapse are related processes and likely involve the same core proteins.

model-of-filopodia-collapse

In neuronal growth cones, filopodia protrusion stops when a repulsive signal binds to its receptor on the cell surface. Receptor-binding transiently inactivates Rac1 GTPase and prevents it from promoting actin assembly. Resumption of Rac1 activity coincides with filopodia collapse and is required for endocytosis of the collapsing plasma membrane and reorganization of F-actin [32]. RhoA and its effector, ROCK, are activated downstream of repulsive cues [31, 32, 33] and their activity has been implicated in reducing actin polymerization following treatment with repulsive signals [34].

Rapid collapse produces a large number of filopodial strands tightly connected to the substrate by long tethers. F-actin bundles [4] and monomeric actin [2] disappear from collapsing filopodia without a compensatory rise in F-actin at the growth cone center; this indicates a net loss of actin rather than a rearward translocation. Furthermore, active nucleation and protrusion of filopodia is still found in discrete areas of collapsing growth cones, which argues against sequestration or modification of actin as the mechanism responsible for the loss of F-actin during the collapse [2]. It has also been shown that filopodial retraction involves periodic helical and rotational motion of the actin shaft, together with the retrograde flow of actin, and these dynamics were together responsible for filopodial shortening during retraction [5]

What regulates filopodia collapse and retraction?

A number of factors regulate collapse and retraction. For example, capping proteins promote filopodial retraction by shielding the barbed end of filaments from further assembly and elongation [6]. Inhibition of F-actin polymerization and protrusion during collapse are mediated by RhoA kinase activity [7]. Collapse may result from the exposure of a “naive” growth cone to a high concentration of a repellent followed by an overactive response [8]. The repulsive component appears to shut down the growth program and is therefore dominant over the growth-stimulating effects of adhesion molecules. In addition, the repellent also interferes with mechanisms that would normally result in filopodial retraction [1].

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References

  1. Bastmeyer M, and Stuermer CA. Behavior of fish retinal growth cones encountering chick caudal tectal membranes: a time-lapse study on growth cone collapse. J. Neurobiol. 1993; 24(1):37-50. [PMID: 8419523]
  2. Fan J, Mansfield SG, Redmond T, Gordon-Weeks PR, and Raper JA. The organization of F-actin and microtubules in growth cones exposed to a brain-derived collapsing factor. J. Cell Biol. 1993; 121(4):867-78. [PMID: 8491778]
  3. Jurney WM, Gallo G, Letourneau PC, and McLoon SC. Rac1-mediated endocytosis during ephrin-A2- and semaphorin 3A-induced growth cone collapse. J. Neurosci. 2002; 22(14):6019-28. [PMID: 12122063]
  4. Zhou FQ, and Cohan CS. Growth cone collapse through coincident loss of actin bundles and leading edge actin without actin depolymerization. J. Cell Biol. 2001; 153(5):1071-84. [PMID: 11381091]
  5. Leijnse N, Oddershede LB, and Bendix PM. Helical buckling of actin inside filopodia generates traction. Proc. Natl. Acad. Sci. U.S.A. 2014; 112(1):136-41. [PMID: 25535347]
  6. Lin CH, Espreafico EM, Mooseker MS, and Forscher P. Myosin drives retrograde F-actin flow in neuronal growth cones. Neuron 1996; 16(4):769-82. [PMID: 8607995]
  7. Gallo G. RhoA-kinase coordinates F-actin organization and myosin II activity during semaphorin-3A-induced axon retraction. J. Cell. Sci. 2006; 119(Pt 16):3413-23. [PMID: 16899819]
  8. Walter J, Allsopp TE, and Bonhoeffer F. A common denominator of growth cone guidance and collapse? Trends Neurosci. 1990; 13(11):447-52. [PMID: 1701577]