Axon guidance: New directions

[Introduction|Part 2|Part 3]

The three studies discussed here make important contributions to our understanding of axon guidance. Lopez-Bendito et al describe a novel guidance mechanism involving tangentially migrating GABAergic interneurons. These cells migrate ventrally from the LGE to form a permissive corridor through the MGE, a region that is otherwise non-permissive for TCAs.

The corridor is fully formed by the time TCAs reach the ventral aspect of the MGE. This is therefore a means by which the presentation of guidance cues can be regulated both spatially and temporally. This may be a more general axon guidance mechanism, as a tangential neuronal migration is also known to precede guidance of axons in the lateral olfactory tract, and may be necessary for pathfinding (Sato et al 1998).

During TCA pathfinding, the growth cone makes a number of steering decisions. It is possible that attractive and repulsive turning is caused by the same mechanisms on opposite sides of the growth cone: an attractive cue leads to actin polymerization on the near side of the growth cone, while a repulsive cue leads to actin polymerization on the far side.

The studies by Tojima et al and Piper et al demonstrate that attraction and repulsion are dependent on distinct mechanisms, both of which occur on the side of the growth cone at which the cue is presented: attraction is dependent on vesicle transport and exocytosis, and repulsion on local translation and endocytosis.

These distinct mechanisms converge on the cytoskeleton. Slit2-induced growth cone collapse requires synthesis of the actin depolymerizing protein cofilin-1 (Piper et al 2006), whereas Netrin-1-induced attractive turning requires translation of asymmetrically localized beta-actin mRNA (Yao et al 2006).

Guidance cues regulate translation positively and negatively, in at least two different ways. Slit2 can activate or inhibit mRNAs and RNA-binding proteins such as elF4E-BP-1 and mTOR (Piper et al 2006), and BDNF causes localization of beta-actin mRNA and zipcode-binding protein ZBP1, which binds to it (Yao et al 2006). Other mechanisms, such as RNA interference, are also likely to be involved.

Exocytosis may initiate the attractive turning response by addng new plasma membrane to the growth cone in the direction of the guidance cue. Conversely, endocytosis might initiate repulsive turning by removeing plasma membrane at the same place.

Exocytosis, endocytosis and protein synthesis may all be involved in growth cone adaptation, whereby the growth cone's sensitivity to guidance cues is recalibrated, a process that is crucial for the detection of concentration gradients and for the steering decisions made at intermediate targets during pathfinding.

The simplest explanation for how adaption occurs is that cell surface receptors are endocytosed following transduction of a guidance signal, causing desensitization of the growth cone. Insertion of newly synthesized receptors into the membrane could then resensitize the growth cone to the cues in its new environment. Exocytosis may be another way in which the distribution of receptors is altered.

Other mechanisms, such as inactivation of membrane-bound receptors and modification of other signalling pathway components, are likely to be involved in growth cone desensitization, as partial replacement of membrane receptors occurs following blockade of translation, but does not cause an increase in sensitivity (Piper et al 2005).

Now, it will be necessary to confirm the role of local translation in vivo. There is no evidence as yet that growth cones contain Golgi stacks or rough endoplasmic reticulum (all of which are required for protein synthesis), or the processing bodies in which RNA interference takes place. Finally, it will be interesting to block translation of different specific mRNAs in the growth cone, and to determine if functionally related groups of mRNAs are translated in response to attractive and repulsive cues.

References:

Piper, M., Anderson, R., Dwivedy, A., Weinl, C., van Horck, F., Mei Leung, K., Cogill, E. & Holt, C. (2006). Signalling mechanism underlying Slit2-induced collapse of Xenopus retinal growth cones. Neuron 49: 215-228.

Piper, M., Salih, S., Weinl, C., Holt, C. E. & Harris, W. A. (2006). Endocytosis-dependent desensitization and protein synthesis-dependent resensitization in retinal growth cone adaptation. Nat. Neurosci. 8: 179- 186.

Sato, Y., Hirati, T., Ogawa, M. & Fujisawa, H., (1998). Requirement for early-generated neurons recognized by monoclonal antiboty lot1 in the formation of lateral olfactory tract. J. Neurosci. 18: 7800-7810.

Tojima, T., Akiyama, H., Itofusa, R., Li, Y., Katayama, H., Miyawaki, A. & Kamaguchi, H. (2006). Attractive axon guidance involves asymmetric membrane transport and exocytosis in the growth cone. Nat. Neurosci. 10: 58-66.

Yao, J., Sasaki, Y., Wen, Z., Bassell, G. J. & Zheng, J. Q. (2006). An essential role for beta-actin mRNA localization and translation in calcium-dependent growth cone guidance. Nat. Neurosci. 9: 1265- 1273.