Netrin-1 mediates neuronal survival through PIKE-L interaction with the dependence receptor UNC5B

Netrins, a family of secreted molecules, have critical functions in axon guidance and cell migration during neuronal development(1,2). In addition to its role as a chemotropic molecule, netrin-1 also acts as a survival factor(3-7). Both UNC5 (that is, UNC5A, UNC5B, UNC5C or UNC5D) and DCC are transmembrane receptors for netrin-1 (refs 8, 9). In the absence of netrin-1, DCC and UNC5 act as dependence receptors and trigger apoptosis(3,6,10). However, how netrin-1 suppresses the apoptotic activity of the receptors remains elusive. Here we show that netrin-1 induces interaction of UNC5B with the brain-specific GtPase PIKe-L. this interaction triggers the activation of PtdIns-3-OH kinase signalling, prevents UNC5B's pro-apoptotic activity and enhances neuronal survival. Moreover, this process relies strongly on Fyn because PIKe-L is tyrosine phosphorylated in response to netrin-1, and the netrin-1-mediated interaction of UNC5B with PIKe-l is inhibited in Fyn-null mice. thus, PIKe-L acts as a downstream survival effector for netrin-1 through UNC5B in the nervous system.