Netrins and their receptors

Abstract

Netrins are a family of proteins that direct cell and axon migration during development. Three secreted netrins (netrin-1, -3 and -4) have been identified in mammals, in addition to two GPI-anchored membrane proteins, netrin-G1 and G2. Orthologues of netrin-1 play a highly conserved role as guidance cues at the midline of the developing CNS of vertebrates and some bilaterally symmetric invertebrates. In vertebrates, floor plate cells at the ventral midline of the embryonic neural tube secrete netrin-1, generating a circumferential gradient of netrin protein in the neuroepithelium. This protein gradient is bifunctional, attracting some axons to the midline and repelling others. Receptors for the secreted netrins include DCC (deleted in colorectal cancer) and the UNC5 homologues: UNC5A, B, C and D in mammals. DCC mediates chemoattraction, while repulsion requires an UNC5 homologue and, in some cases, DCC. The netrin-G proteins bind NGLs (netrin G ligands), single pass transmembrane proteins unrelated to either DCC or the UNC5 homologues. Netrin function is not limited to the developing CNS midline. Various netrins direct cell and axon migration throughout the embryonic CNS, and in some cases continue to be expressed in the mature nervous system. Furthermore, although initially identified for their ability to guide axons, functional roles for netrins have now been identified outside the nervous system where they influence tissue morphogenesis by directing cell migration and regulating cell-cell and cell-matrix adhesion.