Growth-cone attraction to netrin-1 is converted to repulsion by laminin-1

Growing axons are guided by both diffusible and substrate-bound factors(1-3 ). Growth cones of retinal neurons exhibit chemoattractive turning towards the diffusible factor netrin-1 in vitro(4) and are guided into the optic ne rve head (ONH) by localized netrin-1 (ref. 5). Here we report that, in Xeno pus, laminin-1 from the extracellular matrix (ECM), converts netrin-mediate d attraction into repulsion. A soluble peptide fragment of laminin-1 (YIGSR ) mimics this laminin-induced conversion. Low levels of cyclic AMP in growt h cones also lead to the conversion of netrin-induced attraction into repul sion(6), and we show that the amount of cAMP decreases in the presence of l aminin-1 or YIGSR, suggesting a possible mechanism for laminin's effect. At the netrin-1-rich ONH, where axons turn sharply to leave the eye, laminin- 1 is confined to the retinal surface. Repulsion from the region in which la minin and netrin are coexpressed may help to drive axons into the region wh ere only netrin is present, providing a mechanism for their escape from the retinal surface. Consistent with this idea, YIGSR peptides applied to the developing retina cause axons to be misdirected at the ONH. These findings indicate that ECM molecules not only promote axon outgrowth, but also modif y the behaviour of growth cones in response to diffusible guidance cues.