Modulation of Axon Guidance

While additional axon guidance cues are known, and more surely remain to be identified, there is still only a small suite of factors in comparison to the high degree of complexity found in the nervous system. Importantly, members of the Slit, semaphoring, and netrin-1s families are multifunctional; their role in attraction or repulsion is defined by the axon population involved and developmental context in which pathfinding occurs. Indeed, some axons can switch responsiveness to a single cue dramatically over time. How is this plasticity achieved? Recently, a number of studies have begun to address how diverse outcomes are generated using the limited repertoire of guidance cues. It is becoming clear that both extrinsic and intrinsic factors modulate the behavior of developing axons, and that integration of signals from multiple guidance pathways is essential to coordinate directional pathfinding.

1.12.5.1 Regulated Gene Expression

Axon guidance cues and their receptors are dynamically expressed in the embryonic nervous system. By controlling when and where transcription occurs, axon guidance can be coordinated in a precise spatiotemporal fashion. Visual system development in the frog Xenopus provides one example. We have seen that in the tadpole, which has laterally placed eyes, all axons cross to the contralateral side of the brain at the optic chiasm. However, after metamorphosis, medialward movement of the eyes results in their visual fields having a degree of overlap. To integrate information from the overlapping visual field, some axons must project to the ipsilateral side of the brain. This is achieved by the expression of repulsive ephrin-B at the chiasm during metamorphosis. Thus, late-born ventrotemporal axons expressing the Eph-B receptor are repelled from the chiasm, and project ipsilaterally (Figure 8a).

1.12.5.2 Post-Transcriptional Control

The activity of guidance ligands and receptors is also controlled at the post-transcriptional level. For example, Slit2 can bind extracellular proteins including laminin and various proteoglycans, which may modulate its activity and presentation. Other instances of post-transcriptional control include alternative splicing, proteolytic cleavage and receptor shedding, receptor inactivation, and selective trafficking.

Selective trafficking of Robo at the midline crossing in Drosophila commissural axons provides a good example for the post-transcriptional control. As we have already mentioned, though these neurons express Robo from an early stage, it is not present on the surface of precrossing axons because of the presence of the Comm, an intracellular sorting receptor, that traffics Robo to lysosomes (Figure 8b; Keleman et al., 2005).

1.12.5.3 Local Translational Control

The discovery of polyribosomes located beneath postsynaptic sites on dendrites (Steward and Levy, 1982; Steward and Fass, 1983) and the identification of various mRNA species specifically localized within dendrites (Garner et al., 1988) suggest that compartmentalized synthesis of protein occurs in neurons. Altough the existence of local translation in dendrites has been widely accepted, the question of whether or not translation occurs in axons has remained more controversial. In invertebrate axons such as the squid giant axon and the marine gastropod Aplysia, all of the necessary components for RNA translation and a variety of mRNA species have been identified (reviewed in Alvarez et al., 2000). In vitro experiments using fractions isolated from squid axons (Ingoglia et al., 1983) and synaptosomes (Ingoglia et al., 1983) have demonstrated that axonal protein can occur in axons. In vertebrates, ribosomes have

Chiasm

Premetamorphosis -only contralateral projections

Chiasm

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