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  • Review Article
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The trip of the tip: understanding the growth cone machinery

Nature Reviews Molecular Cell Biology volume 10, pages 332–343 (2009)Cite this article

Key Points

  • During axon guidance, the growth cone, which comprises both the 'vehicle' and the 'navigator', progresses through stages of protrusion, engorgement and consolidation to move forward in a spatially directed manner.

  • Growth cone guidance is an integrated process that requires both substrate-bound cues (such as cell adhesion molecules (CAMs), laminin and fibronectin) to provide the 'road' for traction, and chemotropic cues (such as netrins and semaphorins) that present 'road signs' for steering directions.

  • Filamentous (F)-actin retrograde flow, which is driven by myosin II contractility in the transition (T) zone, and F-actin bundle treadmilling keep the growth cone engine idling and thus responsive to directional cues. Growth cone receptor binding to an adhesive substrate leads to the formation of a complex that acts like a molecular 'clutch', which mechanically couples receptors and F-actin to stop retrograde flow and drives actin-based forward growth cone protrusion.

  • Microtubules (MTs) have a role in steering the growth cone vehicle; individual peripheral (P) domain MTs might act as guidance sensors and carry signals to and from receptor binding sites, and bulk central (C) domain MTs steer growth cone advance.

  • Live imaging studies suggest that the function of actin dynamics is to guide and control MTs to steer the growth cone in the right direction, and interactions between actin and MTs are tightly regulated. F-actin bundles regulate the activities of exploratory MTs, whereas F-actin arcs constrain C domain MTs.

  • For spatial discontinuities in the environment to drive growth cone steering and, in particular, to accurately interpret numerous cues simultaneously, the growth cone navigation system integrates and translates the multiple environmental directions to locally modulate the dynamics of the cytoskeletal machinery. The Rho family of GTPases control cytoskeletal dynamics downstream of nearly all guidance signalling pathways, and they are spatially regulated by guanine nucleotide-exchange factors (GEFs) and GTPase-activating proteins (GAPs). Localized control of actin dynamics at the leading edge through actin-binding proteins, and coordination of MT–actin crosslinking, are two key outputs of the navigation system that are required for growth cone steering.

Abstract

The central component in the road trip of axon guidance is the growth cone, a dynamic structure that is located at the tip of the growing axon. During its journey, the growth cone comprises both 'vehicle' and 'navigator'. Whereas the 'vehicle' maintains growth cone movement and contains the cytoskeletal structural elements of its framework, a motor to move forward and a mechanism to provide traction on the 'road', the 'navigator' aspect guides this system with spatial bias to translate environmental signals into directional movement. The understanding of the functions and regulation of the vehicle and navigator provides new insights into the cell biology of growth cone guidance.

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Figure 1: Directions for the trip.
Figure 2: The growth cone 'vehicle'.
Figure 3: The growth cone as a 'navigator'.

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Acknowledgements

Owing to space limitations, only a selection of relevant papers were referenced. We thank J. Flanagan and C. Dubreuil for helpful suggestions on this manuscript. D.V.V. is supported by NS035909. L.A.L. is supported by a National Institutes of Health (NIH) National Research Service Award (NRSA) postdoctoral fellowship.

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    Laura Anne Lowery & David Van Vactor

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Glossary

Chemotropic cue

An external chemical cue, often found in a gradient, that leads to a directional growth in response.

Protrusion

The stage of growth cone progression in which there is extension of filopodia and lamellipodia-like veils.

Engorgement

The stage of growth cone progression in which microtubules further invade into the growth cone, fixing the new axonal growth direction.

Consolidation

The stage of growth cone progression in which actin filaments at the neck of the growth cone depolymerize and the membrane shrinks to form a cylindrical axon shaft around the bundle of microtubules.

Actin treadmilling

The process by which the continual addition of actin subunits at the barbed end of an actin polymer and disassembly of the polymer at the pointed end ensures that the polymer stays of constant length, but individual subunits move along.

Filopodium

A thin, transient actin protrusion that extends from the cell surface and is formed by the elongation of bundled actin filaments in its core.

Lamellipodia-like veil

A thin, sheet-like extension of cytoplasm between filopodia that is formed by branched actin networks.

F-actin bundle

Long actin filaments that are crosslinked together in parallel, forming the core of filopodia.

F-actin arc

An actomyosin contractile structure that is perpendicular to bundles of actin, forming a hemicircumferential ring in the transition zone.

Dynamic instability

The state used to describe microtubule polymer dynamics, in which microtubule polymers cycle through periods of growth, shrinkage and occasional pausing.

Actin network

Actin filaments that are crosslinked in a branched pattern, forming the structure of lamellipodia-like veils.

Neuroblastoma

A tumour derived from primitive ganglion cells that can partially differentiate into cells that have the appearance of immature neurons.

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Lowery, L., Vactor, D. The trip of the tip: understanding the growth cone machinery. Nat Rev Mol Cell Biol 10, 332–343 (2009). https://doi.org/10.1038/nrm2679

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