Where the rubber meets the road: netrin expression and function in developing and adult nervous systems

Netrins are a family of secreted proteins that direct the migration of cells and axonal growth cones during neural development. They are bifunctional cues, attracting some cell types and repelling others. Netrins function as either short- or long-range cues, in some circumstances acting close to the surface of the cells that produce them and in other cases at a distance. Two classes of receptors mediate the response to netrin-1, the deleted in colorectal cancer family and the UNC-5 homolog family. Although netrin function has been extensively studied in the embryonic nervous system, netrin-1 is expressed in the adult mammalian spinal cord at a level similar to that in the embryonic CNS. In the adult and embryonic CNS, the majority of netrin-1 protein is not freely soluble but is associated with membranes and extracellular matrix. This distribution is consistent with netrin-1 acting as a short-range cue. Here we present a model whereby netrin-1 in the embryonic neural epithelium could act as a membrane-associated long-range cue. Netrin-1 is expressed in the adult by multiple types of neurons and by myelinating glia: oligodendrocytes in the CNS and Schwann cells in the PNS. In the white matter of the adult CNS, netrin-1 protein is absent from compact myelin but enriched in periaxonal myelin at the interface between axons and oligodendrocytes. This distribution suggests that in the adult nervous system netrin-1 may function to mediate cell-cell interactions. Furthermore, netrin receptor expression persists in neurons following injury, raising the possibility that netrin-1 may influence axonal regeneration.