Cytoskeleton in Axon Growth

Michael Stiess, Max Planck Institute of Neurobiology, Martinsried, Germany
Frank Bradke, Max Planck Institute of Neurobiology, Martinsried, Germany

Published online: December 2009

DOI: 10.1002/9780470015902.a0021855

During development, neurons extend two different types of processes, typically several short dendrites and one long axon. The axon forms synapses with dendrites of other neurons to integrate into a neuronal network. Axons can extend to enormous lengths. Their growth is guided and exactly controlled to guarantee the correct neuronal connections. Microtubules and actin filaments, the two major cytoskeletal elements, are the key players in these processes. They form the backbone for axon extension, provide the construction material for axon elongation, and are the site of convergence of extracellular and intrinsic signals. Correct path finding of the axon is ensured by a specialized and highly dynamic structure at the tip of the growing axon, the growth cone. Its dynamic cytoskeleton is the machinery that establishes, controls and directs axon growth. Overall, the cytoskeleton determines the distinction of axons and dendrites and aberrant changes in the cytoskeleton are a major cause of regenerative failure after spinal cord injury.

Key concepts:

  • The growth cone is the highly motile tip of a growing axon, where the axon becomes elongated.
  • Growth cone motility is regulated by cytoskeletal dynamics.
  • Actin filaments determine growth cone shape and are involved in path finding.
  • Microtubules give structure to the axon shaft and are essential for axon elongation.
  • Guidance cues act on the cytoskeleton in the growth cone.
  • A dynamic interaction between actin filaments and microtubules is necessary to steer axon growth.
  • The cytoskeleton regulates neuronal polarity.
  • Injury induced pathological changes of the cytoskeleton are a major cause for lack of regeneration after spinal cord injury.

Keywords: neuron; axon growth; growth cone; cytoskeleton; actin filaments; microtubules

Figure 1. The growth cone. (a) Growth cone of a hippocampal neuron. The actin cytoskeleton is visualized by fluorescently labelled phalloidin (red). Microtubules are stained with antibodies against tubulin (green). The peripheral domain of the growth cone shows the typical actin bundles while microtubules dominate the central domain of the growth cone and the axon shaft. Scale bar, 10 m. (b) Schematic diagram of a growth cone. The growth cone can be divided into three domains: The peripheral domain (P-domain) comprises of the finger-like filopodia that are separated by membrane veils called lamellipodia. Filopodia are formed by F-actin bundles while lamellipodia are based on an F-actin meshwork. The central domain (C-domain) is filled with microtubules that enter the growth cone bundled from the axon shaft. Single, dynamic microtubules explore the peripheral domain. In between the P- and C-domain lies the transition zone (T-zone). Here, actin–myosin structures form F-actin arcs that surround the C-domain and are perpendicular to the F-actin bundles.
Figure 2. Stages of axon growth. The process of axon growth can be divided into three different steps. (a) Protrusion: Actin filament polymerization is enhanced at the leading edge. This leads to extension of filopodia and lamellipodia. Actin clears from the corridor between the P- and C-domain. (b) Engorgement: Microtubules of the C-domain invade the free corridor towards the site of new growth. Through the forward movement of the C-domain, this region also becomes enriched with vesicles and organelles. (c) Consolidation: In the last step, microtubules become bundled and actin protrusion becomes repressed in the proximal part of the growth cone. Thereby, the proximal part assumes cylindrical shape and is integrated in the axon shaft.
Figure 3. Dynamics of actin filaments. Actin filaments grow by adding ATP-actin (red) to the barbed end, which faces the distal membrane in the growth cone. ADP-actin (green) becomes disassembled from the filament at the pointed end that faces the T-zone. Polymerization at the distal membrane and depolymerization in the T-zone lead to treadmilling of F-actin. ADP-actin becomes recycled to ATP-actin and can be used again for polymerization. Actin-binding proteins (ABPs) regulate these dynamics by either promoting polymerization like Ena/Vasp proteins or by severing and depolymerizing F-actin like ADF/cofilin. Furthermore, ABPs can organize the actin filaments into higher order structures, for example, by bundling through proteins like fascin.
Figure 4. Dynamics of microtubules. Microtubules are intrinsically dynamic. The polymers rapidly switch from a shrinking mode to a growing mode (rescue) or the reverse way (catastrophe). Microtubule-associated proteins (MAPs) regulate microtubule dynamics. For instance, CRMP-2 and plus-end tracking proteins (+TIPs) promote microtubule assembly. In contrast, SCG10 and stathmin destabilize microtubules. Furthermore, proteins like katanin or spastin sever microtubules and are therefore important in axon growth and branching.
Figure 5. The role of the cytoskeleton in neuronal polarity. At the beginning of neuronal development, a neuron has several equal processes. During neuronal polarization, intracellular signalling pathways change the cytoskeleton in one of these processes, the future axon. The actin cytoskeleton in the growth cone becomes more dynamic and thus, actin filaments do not function anymore as a barrier to protruding microtubules. Thus, the growth cone can advance and the axon forms. At the same time, microtubules are stabilized in the axon. These stable microtubules may serve as tracks for specific axonal transport and promote further axonal and somatodendritic segregation. In the nongrowing processes, the actin filaments form a rigid barrier in the growth cone that prevents the protrusion of microtubules into the peripheral domain. Thus, this actin barrier inhibits the growth of the other processes, the future dendrites.
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Related Sub-Topics:

Neurons | Intracellular and Extracellular Signalling | Cell Cytoskeleton | Growth and Synthesis | Cell Shape | Genes, Molecules and Cellular Processes | Development of Vertebrate Nervous System
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Article Title: Cytoskeleton in Axon Growth
 
How to Cite close
Stiess, Michael, and Bradke, Frank(Dec 2009) Cytoskeleton in Axon Growth. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021855]