Axon Guidance

Abstract

Axon guidance is the means whereby axon processes growing from differentiating nerve cells are guided to their targets during embryonic development. The growing axon tip, the growth cone, is essential to this process, being capable of locomotion and responding to molecular cues in its cellular environment. A knowledge of the interaction of actin microfilaments and tubulin microtubules of the growth cone cytoskeleton is necessary to understand the dynamic properties of the growth cone. External guidance cues may be attractive or repulsive, and have been shown to fall into diverse molecular families. The signalling pathways that they trigger in the growth cone are being elucidated. Defects in axon guidance may underlie various abnormalities of nervous system development in humans.

Key Concepts:

  • The growth cone is both a motile and sensory apparatus for axon guidance.

  • The growth cone cytoskeleton is divided into three regions that mediate distinct aspects of actin–tubulin dynamics.

  • Regulation of actin assembly and disassembly is important for growth cone locomotion.

  • Microtubules provide structural support and are responsible for transport of organelles and molecules to and from the growth cone.

  • Dynamic microtubules are considered to play an instructive role in growth cone turning.

  • There are two classes of growth cone guidance cue in the cellular environment; attractive/permissive or inhibitory/repulsive. Both classes include members that can act over short distances and members that can act over long distances.

  • A diverse group of molecular families that mediate guidance has been identified, including members of the immunoglobulin superfamily, cadherins, netrins, Slits, semaphorins and Eph/ephrins.

  • Growth cone responses to external cues are mediated by molecular signals such as mitogen‐activated protein kinases (MAPK), calcium ions, cyclic nucleotides and the Rho subfamily of small GTPases, which affect cytoskeletal dynamics.

Keywords: axon guidance; growth cone; cell adhesion; chemoattraction; repulsion

Figure 1.

Structure of the axon growth cone, showing the major features of the growth cone. Note that the filopodia and lamellipodia, with their associated actin microfilaments, make up the P domain, while microtubules and organelles, such as mitochondria, are present in the C domain. The transition zone (T zone) is sited at the interface between the C and P domains, where dynamic microtubules interact with the microfilaments. Although a diagram inevitably portrays the growth cone as a static structure, in vivo it is highly dynamic.

Figure 2.

Orientation and structure of cell‐adhesion molecules (CAMs) at the cell surface. The examples shown are neural CAM (NCAM) (see text) and myelin‐associated glycoprotein (MAG), members of the immunoglobulin superfamily that mediate calcium‐independent adhesion, and N‐cadherin, a molecule mediating calcium‐dependent adhesion. In addition to the immunoglobulin (Ig) domains, NCAM contains two fibronectin repeats, and its transmembrane form is depicted here. The extracellular part of N‐cadherin contains five ectodomains: three with internal homology (dark block symbols), and two less homologous repeats (lighter block symbols).

Figure 3.

Major classes of axon guidance molecules and their receptors. Lam, region with homology to N‐terminal domains of laminin chains; EGF, epidermal growth factor repeat; B+, basic domain; Ig, immunoglobulin domain; FN, fibronectin type III domain; TS, thrombospondin type I domain; CT, cysteine terminal knot; LamG, laminin G domain; LRR, leucine rich repeat; Sema, semaphorin domain; IPT, Ig‐like, plexins, transcription factors; CUB, complement/sea urchin – EGF/BMP1 domain; C, coagulation factor homology domain; MAM, meprin/A5/PTPmu domain; GPI, glycophosphatidylinositol linkage; CYS, cysteine‐rich domain; TK, tyrosine kinase domain.

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References

Brunet I, Weinl C, Piper M et al. (2005) The transcription factor Engrailed‐2 guides retinal axons. Nature 438: 94–98.

Buck KB and Zheng JQ (2002) Growth cone turning induced by direct local modification of microtubule dynamics. Journal of Neuroscience 22: 9358–9367.

Campbell DS and Holt CE (2001) Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation. Neuron 32: 1013–1026.

Charron F and Tessier‐Lavigne M (2007) The Hedgehog, TGF‐beta/BMP and Wnt families of morphogens in axon guidance. Advances in Experimental Medicine and Biology 621: 116–133.

Jung H, O'Hare CM and Holt CE (2011) Translational regulation in growth cones. Current Opinion in Genetics and Development 21: 458–464.

Salinas PC and Zou Y (2008) Wnt signaling in neural circuit assembly. Annual Review of Neuroscience 31: 339–358.

Further Reading

Araújo SJ and Tear G (2003) Axon guidance mechanisms and molecules: lessons from invertebrates. Nature Reviews Neuroscience 4: 910–922.

Brown MC, Keynes RJ and Lumsden A (2001) The Developing Brain. Oxford: University Press.

Chédotal A (2011) Further tales of the midline. Current Opinion in Neurobiology 21: 68–75.

Dickson B (2003) Molecular mechanisms of axon guidance. Science 298: 1959–1964.

Krull CE and Eisen JS (2010) Mechanisms of growth cone repulsion. F1000 Biology Reports 2: 6.

Lowery LA and Van Vactor D (2009) The trip of the tip: understanding the growth cone machinery. Nature Reviews Molecular Cell Biology 10: 332–343.

Sanes DH, Reh TA and Harris WA (2012) Development of the Nervous System, 3rd edn. Burlington, MA and Oxford, UK: Academic Press.

Tessier‐Lavigne M and Kolodkin A (2011) Neuronal Guidance. The Biology of Brain Wiring. New York: Cold Spring Harbor Laboratory Press.

Tojima T, Hines JH, Henley JR and Kamiguchi H (2011) Second messengers and membrane trafficking direct and organize growth cone steering. Nature Reviews Neuroscience 12: 191–203.

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How to Cite close
Piper, Michael J, Keynes, Roger J, and Cook, Geoffrey MW(Mar 2012) Axon Guidance. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000799.pub3]