Members of the semaphorin family have been implicated in mediating axonal guidance in the nervous system by their ability to collapse growth cones and to function as chemorepellents. The present findings show that recombinant Semaphorin D has similar effects on cortical axons and, in addition, inhibits axonal branching. In contrast, semaphorin E acts as an attractive guidance signal for cortical axons. Attractive effects were only observed when growth cones encountered increasing concentrations or a patterned distribution of Semaphorin E, but not when they are exposed to uniform concentrations of this molecule. Specific binding sites for Semaphorin D and Semaphorin E were present on cortical fibers both in vitro and in vivo at the time when corticofugal projections are established. In situ hybridization analysis revealed that the population of cortical neurons used in our experiments express neuropilin-1 and neuropilin-2, which are essential components of receptors for the class III semaphorins. Moreover, semD mRNA was detected in the ventricular zone of the neocortex whereas semE mRNA was restricted to the subventricular zone. Taken together, these results indicate that semaphorins are bifunctional molecules whose effects depend on their spatial distribution. The coordinated expression of different semaphorins, together with their specific activities on cortical axons, suggests that multiple guidance signals contribute to the formation of precise corticofugal pathways.

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