Signalling mechanisms mediating neuronal responses to guidance cues

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Abstract
Neuronal migration and axon pathfinding are guided by extracellular cues, including netrins, semaphorins, ephrins and Slits. This review focuses on the signalling mechanisms that underlie axon guidance and neuronal migration in the vertebrate nervous system. There are several classical models of axon projection and neuronal migration in vertebrates, including the retinotectal projection, the commissural axons of the spinal cord, the radially migrating neuronal precursors in the neocortex, and the tangentially migrating neurons in the rostral migratory stream. Actin assembly is a key process that controls the growth and steering of axon growth cones (although recent evidence also supports a role for microtubules). The Rho family of small GTPases, which includes Rho, Rac and Cdc42, have important roles in regulating actin cytoskeletal dynamics and have been implicated in growth cone guidance. Netrins were the first family of directional guidance cues to be found in both invertebrate and vertebrate nervous systems. Netrin-1 and netrin-2 were identified as floor-plate-derived promoters of commissural axon outgrowth. A single netrin can be attractive to some axons and repulsive to others. Semaphorins are a family of secreted and membrane-associates proteins that can mediate axon repulsion and growth cone collapse. They have also been implicated in immune responses. Ephrins are membrane-associated guidance molecules, and are divided into two classes (A and B) on the basis of their mechanism of membrane association. The Eph proteins were originally defined as the receptors for the ephrins, but they can also act as ephrin ligands. Slits are axon repellents, and they are also important for neuronal migration. Roundabout (Robo) is a cell surface receptor that is responsible for the repulsive effect of Slit. The chemokine stromal-derived factor 1 (Sdf1) is involved in axon guidance and neuronal migration. Sdf1 is expressed in the meninges surrounding the cerebellum, and it prevents premature migration of granule cells into the inner layer by anchoring them in the external layer. Recent reports have implicated several well-known morphogens in axon guidance, including sonic hedgehog, bone morphogenetic proteins and the Wnt family of secreted proteins. Different signals have to be integrated in the growth cone to reach an appropriate response and this requires crosstalk between the signalling pathways; for example, through receptor–receptor interaction, regulation of the RhoGTPases or modulation of intracellular levels of second messengers.