Posted by: Dan | July 1, 2006

Axon Guidance: perspectives and relation to other observations of cell migration

For a review of the various elements of axon guidance, Maskery & Shinbrot is perhaps the most comprehensive resource out there for a current knowledgebase. At the center of discussion is usually the complex marvel known as the growth cone, which is a sensory motile structure responsible for leading its axon through a complex extracellular milieu to its final target.

Spacio-temporal patterns of an array of guidance cues make deciphering of the growth cone’s behavior difficult though. Maskery & Shinbrot note that the “Experimental literature on [a mechanistic understanding of… growth cone and axonal pathfinding strategies] is voluminous, and a comprehensive discussion” can be found in the other three reviews cited below.

First of all, as in other migrating cells, both the actin and microtubule cytoskeleton components play distinct and indespensible roles in advancement of the leading edge, including a cooperative role in forming and stabilizing lamellipodial and filopodial extenstions. As such, Rho-family GTPases and cytoskeleton-regulatory proteins play a major role in growth cone behavior.
growth cone
What is more (but not exclusively) neuronal specific, are the four major classes of guidance molecules identified by molecular biology: the semaphorins, the netrins, the slits, and the ephrins, studied in vitro for the most part, as of yet. Of these, there are attractant and repellant cues in each group (even for a given molecule, depending on the cellular context), they act on different length-scales in different contexts, and the relative impacts of multiple concurrent cues in the in vivo situation remains a mystery.

Regarding overall patterns of guidance behavior though:

Most of the movement is relatively straightforward until one has to make a decision to exit or stay on the highway. Neurites typically make this decision in particular regions, termed decision regions. This term, first coined in 1985 to describe regions in the motor neuron pathway where growth cones from different axonal populations diverged to follow different paths, is stil used to describe a region where different growth cone populations exhibit diverging directional preferences. In general, within decision regions growth cone morphology becomes more complex, filopodial number increases, and growth cone migration becomes more erratic.

…growth cone migration appears to follow two basic patterns: simple streamlined outgrowth with few migrational pauses in non-decision regions and more erratic outgrowth in addition to complex morphology within decision regions.

The role of decision regions vastly complicates the deciphering of the interactions between growth cone populations and extracellular milieu, and how each axon is able to find its target, when the guidance cue repertoire is so similar for the rest of the growth cone population.
guidance determinism
Regardless, Maskery and Shinbrot describe a biphasic model of axon guidance, where competing deterministic (simple streamlined outgrowth) and stochastic (non-deterministic, erratic outgrowth; random walk) behavoirs are balanced, as with the analogy of the blind woman analogy:

… neither wandering rapidly nor charging forward permits a controlled response, and only if these two influences are balanced can guidance operate reliably.

And yes, how these factors are balanced is unclear. Deterministic behavior can simply be described as an insensitivity to guidance cues, wherease Stochastic is used to describe apparently random, unspecified behavior.

The real questions are ‘How are Deterministic/Stochastic behaviors balanced,’ ‘How do combinations of guidance cues mechanistically specify direction,’ and ‘How do these cues regulate the cytoskeletal machinery?’

References:

  • Deterministic and stochastic elements of axonal guidance. Maskery S, Shinbrot T. Annu Rev Biomed Eng. 2005; 7:187-221. Pubmed.
  • Signaling at the growth cone: ligand-receptor complexes and the control of axon growth and guidance. Huber AB, Kolodkin AL, Ginty DD, Cloutier JF. Annu Rev Neurosci. 2003; 26:509-63. Epub 2003 Mar 28. Pubmed.
  • Axon guidance: receptor complexes and signaling mechanisms. Grunwald IC, Klein R. Curr Opin Neurobiol. 2002 Jun; 12(3):250-9. Pubmed.
  • Signalling mechanisms mediating neuronal responses to guidance cues. Guan KL, Rao Y. Nat Rev Neurosci. 2003 Dec; 4(12):941-56. Pubmed.

Responses

  1. Great post.
    Very infomative, thanks!


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