A ROLE FOR NETRIN-1 IN THE GUIDANCE OF CORTICAL EFFERENTS

An intermediate target for axons lea ring the cerebral cortex in embry onic mammals is the ganglionic eminence (GE), the embryonic precursor of the basal ganglia. The cues that direct these axons over the initia l portion of their trajectory are not well understood, but could inclu de both short-range and long-range attractants and repellents. In the present study, we provide evidence that corticofugal axons might be gu ided at least partly by a diffusible factor or factors originating in the lateral GE and the sulcus between the lateral and medial ridges of the GE (ISS), as well as evidence implicating the axonal chemoattract ant netrin-1 in mediating these effects. Explants of lateral GE and IS S obtained from E12.5 and E13.5 mouse forebrain have a strong effect o n both the outgrowth and orientation of corticofugal axons when cultur ed at a distance with explants of embryonic cortex in collagen gels, N etrin-1 mRNA is detected in these target tissues by in situ hybridizat ion, and both netrin-1 protein and heterologous cells secreting netrin -1 can mimic the outgrowth-promoting effect of these target tissues in vitro, Furthermore, the growth of corticofugal axons is oriented towa rd an ectopic source of netrin-1 in vitro, and a function blocking ant i-netrin-1 antiserum specifically abolishes the cortical axon outgrowt h elicited by explants of lateral GE and the ISS in collagen gel cocul tures. Taken together, these results suggest a role for netrin-1 in th e attraction at a distance of early cortical axons by the GE. Thus in mammals - as is also observed in nematodes the development of non-comm issural projections in anterior regions of the embryo might be directe d by mechanisms similar to those involved in directing the development of commissural projections in more posterior regions of the central n ervous system.