Background information
Netrin proteins are a family of laminin-related secreted proteins that provide guidance signals for axonal growth and cell migration during development. Netrin-1, which is the mammalian homolog of UNC-6 from C. elegans, is largely expressed in the developing nervous system and in mesodermal tissues. Netrin-1 is expressed by the floor plate as either a cell associated protein or in a diffusible form, and it binds to several surface receptor components, including deleted in colorectal cancer (DCC) and neogenin. During embryonic development, netrin-1 diffuses through the neuronal epithelium, where it forms a chemoattractant gradient that directs axonal migration to the ventral midline of the spinal cord. Netrin-2 and the corresponding mouse homolog netrin-3 are expressed primarily in the lower two-thirds of the spinal cord, and, like netrin-1, they can either attract or repel commissural axons at a distance. Netrin signaling is dependent on the concentration of calcium outside the cell and the level of PKA activity. In axonal cells, a reduction in PKA activity converts the responsiveness of the axons to the netrin proteins, as the cells are repelled, rather than attracted, by the netrin gradient.
