Neuronal connections are formed by the extension of axons, which migrate to reach their synaptic targets. The axonal growth cone, located at the axon leading edge, contains receptors that sense attractive and repulsive guidance cues, which help navigate the axon to its final destination.
Four major families of attractive and repulsive guidance cues and receptors have been identified: 1) Netrins and DCC and UNC-5 receptors, 2) Slits and Robo receptors, 3) Semaphorins and plexin and neurophilin receptors and, 4) Ephrins and Eph receptors. In addition, more recently, Shh, BMP, and Wnt been implicated in growth cone guidance.
Netrins, Slits, and some Semaphorins are secreted proteins that associate with cells or the extracellular matrix, whereas Ephrins and other Semaphorins are anchored to the cell surface. Many guidance cues are bifunctional, producing an attractive response for some growth cones, while acting as repulsive guidance cue in other contexts. Guidance receptors signal as multimeric complexes. Some receptors are relatively specific for a particular function: for example, UNC-5 is only known to act in netrin repulsion. Other receptors are more promiscuous, interacting with multiple partners in a variety of signaling events. Attractive cues promote actin polymerization and axon extension, whereas repulsive cues decrease actin polymerization, resulting in growth cone collapse and axon retraction. The Rho family of GTPases, which regulates the formation of a wide range of cytoskeletal structures, is strongly implicated in axonal guidance.