Directional information is provided to migrating neurons and growth cones in the form of extracellular cues, whose presence, absence, or concentration differential is transduced into cytoskeletal changes that affect motility. Among the best-characterized secreted guidance cues are the netrins, semaphorins, ephrins and slit protein families. Several of these factors are bifunctional, producing positive growth and guidance effects on some growth cone populations and negative effects on others.
Netrins comprise a phylogenetically conserved family of guidance cues related to the extracellular matrix molecule laminin. Netrins are secreted from the floor plate and ventral spinal cord and act as a chemoattractant for commissural axons. They are bifunctional and attract some axons and repel others. Netrin-induced attraction is mediated by the DCC (Deleted in Colorectal Cancer) family of receptors. Netrin engagement causes multimerization of DCC receptors, mediated by the association of P3 regions. The intracellular domain of UNC5 consists of several recognizable domains, including a death domain, which is found in many apoptosis regulating proteins, a ZU5 domain, which is also present in the GAP junction protein ZO1, and a DCC-binding domain, which has an important role in mediating its interaction with DCC. DCC is required for both the attractive and repulsive responses, whereas UNC5 is required only for the repulsion of some axons.
Activation of DCC and DCC-UNC5 by Netrin1 triggers two different cyclic nucleotide signaling pathways. In the absence of UNC5, DCC activation triggers a cAMP dependent signaling pathway and enhances CaCn ion channel activity. Enhanced Ca2+ entry, together with additional Ca2+ release from RyRs creates a high level of intracellular Ca2+, favoring growth-cone attraction. In the presence of UNC5, Netrin1 activation of DCC-UNC5 triggers cGMP signaling. This results in decreased Ca2+ currents and growth-cone repulsion. In addition to their roles in axon guidance, netrins also influence the peripheral projections of motor axons to their target muscles. Caln and NFAT have recently been found to act downstream of the DCC receptor to promote axon outgrowth.