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  • Review Article
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Actin-binding proteins take the reins in growth cones

Nature Reviews Neuroscience volume 9, pages 136–147 (2008)Cite this article

Key Points

  • To be effective in enabling growth-cone motility, actin filaments must be organized into higher-order assemblies with distinct architectures (actin superstructures).

  • Actin superstructures are self-organizing. The cell-free Listeria monocytogenes comet-tail reconstitution assay demonstrated that a propulsive and dynamic actin superstructure can be self-organized by an ensemble of actin-binding proteins. Although they are classically defined only by their architectural appearance, actin superstructures can now be more subtly distinguished by their recruitment of specific ensembles of actin-binding proteins.

  • Actin superstructure organization effectively occurs in a two-step process. As actin superstructures are self-organizing, the limiting step is actin-filament assembly itself. Not all of the proteins that are involved in generating or maintaining actin superstructures have been well characterized in growth cones.

  • Leading-edge actin superstructures are organised into stratified layers. Because actin subunits incorporate into filaments at the leading-edge membrane, migrate away from the membrane at similar rates, and undergo ATP hydrolysis and Pi release on an average time scale, actin superstructures can be divided into layers or strata based on the enrichment of specific actin–nucleotide complexes or the enriched binding of certain actin-binding proteins.

  • A single actin-binding protein alone can support either an attractive or a repulsive turn. In Xenopus laevis spinal neuronal growth cones, a gradient of bone morphogenetic protein 7 (BMP7) can cause either an attractive or a repulsive turn through the bidirectional phospho-regulation of the actin-binding protein cofilin. Attractive turning requires the activation of a kinase pathway, whereas repulsive turning requires the activation of a Ca2+-dependent phosphatase pathway. Thus, actin-binding proteins can function as effective 'signal integrators' of signalling pathways.

  • Distinct but spatially overlapping actin superstructures exist. With the advent of fluorescent speckle microscopy, dynamic characteristics of actin superstructures can be measured and used to identify distinct but spatially overlapping superstructures. In migrating non-neuronal cells, the generation and maintenance of distinct but overlapping superstructures requires the tropomyosin proteins, and although distinct but overlapping superstructures have not been identified in growth cones, all of the required components are present.

  • Actin superstructures have not been described in dystrophic growth cones. In response to axotomy, the tips of CNS axons undergo a morphological change to become dystrophic growth cones. Although actin has been suggested to be a potential target for regenerative therapy, it is not even clear whether actin superstructures are reassembled in dystrophic growth cones.

  • New approaches, ideas and technologies should be considered in the study of actin-based growth-cone motility. In recognizing that actin superstructure organization occurs in a two-step process, two outstanding issues become clear. First, the mechanisms that control actin nucleation and growth require further characterization in growth cones. Second, the proteome of actin-binding proteins that underlie unique actin superstructures should be determined for growth cones. Emerging micro- and nano-technologies should greatly facilitate future studies.

Abstract

Higher-order actin-based networks (actin superstructures) are important for growth-cone motility and guidance. Principles for generating, organizing and remodelling actin superstructures have emerged from recent findings in cell-free systems, non-neuronal cells and growth cones. This Review examines how actin superstructures are initiated de novo at the leading-edge membrane and how the spontaneous organization of actin superstructures is driven by ensembles of actin-binding proteins. How the regulation of actin-binding proteins can affect growth-cone turning and axonal regeneration is also discussed.

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Figure 1: Actin superstructures in a model growth cone.
Figure 2: The geometry of superstructure strata is determined by the organizational plane of actin nucleators.
Figure 3: The bidirectional phospho-regulation of cofilin determines the turning response of growth cones from Xenopus laevis spinal-cord neurons to a gradient of BMP7.
Figure 4: Distinct but spatially overlapping actin superstructures of lamellae and lamellipodia.

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Acknowledgements

The authors would like to thank K. Hite and E. Peterson for valuable discussions and critical reading of the manuscript, and the National Science Foundation grant DGE0234615 (C.W.P.) and National Institutes of Health grants NS48660 (K.C.F.) and NS40371 (J.R.B.) for financial support.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, 80523, Colorado, USA

    Chi W. Pak

  2. Graduate Program in Cell and Molecular Biology, Colorado State University, Fort Collins, 80523, Colorado, USA

    Kevin C. Flynn

  3. Molecular, Cellular and Integrative Neuroscience Program, Colorado State University, Fort Collins, 80523, Colorado, USA

    James R. Bamburg

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  1. Chi W. Pak
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  2. Kevin C. Flynn
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  3. James R. Bamburg
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Correspondence to James R. Bamburg.

Glossary

Barbed end

The end of an actin filament that polymerizes faster when the actin-monomer concentration is high and that also polymerizes at steady-state.

Pointed end

The end of an actin filament that polymerizes slower when the actin-monomer concentration is high and that depolymerizes at steady state.

Lamellipodium

A specific leading-edge cellular protrusion that is characterized by branched actin filaments, the absence of high-molecular-weight tropomyosins and the presence of cofilin. It is localized within 1–2 μm of the leading edge. Actin speckles in lamellipodia undergo fast retrograde flow and are short-lived. Mesh-like actin-based protrusions in neuronal growth cones are sometimes referred to as lamellipodia.

Actin speckle

Fluorescently-tagged actin monomers that appear as single diffraction-limited molecules when expressed in cells at a low concentration.

Lamellum

A leading-edge cellular protrusion that is characterized by the presence of less-branched actin filaments than those in lamellipodia and the recruitment of high-molecular-weight (HMW) tropomyosins and myosin. It is localized within 2–5 microns of the leading edge. Actin speckles in the lamellae undergo slower retrograde flow and are longer-lived than those in lamellipodia.

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Pak, C., Flynn, K. & Bamburg, J. Actin-binding proteins take the reins in growth cones. Nat Rev Neurosci 9, 136–147 (2008). https://doi.org/10.1038/nrn2236

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