The Slits are secreted proteins that bind to Robo receptors and play a role
in axon guidance and neuronal migration. In vertebrates, Slit2 is a major
chemorepellent for developing axons and is involved in the control of midli
ne crossing. In vivo, Slit2 is cleaved into 140 kDa N-terminal (Slit2-N) an
d 55-60 kDa C-terminal (Slit2-C) fragments, although the uncleaved/full-len
gth form can also be isolated from brain extract. We explored the functiona
l activities of Slit2 fragments by engineering mutant and truncated version
s of Slit2 representing the N-, C-, and full/uncleavable (Slit2-U) fragment
s. Only Slit2-N and Slit2-U bind the Robo proteins. We found that in collag
en gel, olfactory bulb (OB) but not dorsal root ganglia (DRG) axons are rep
elled by Slit2-N and Slit2-U. Moreover, only Slit2-N membranes or purified
protein-induced OB growth cones collapse. Finally, we found that only recom
binant Slit2-N could induce branching of DRG axons and that this effect was
antagonized by Slit2-U. Therefore, different axons have distinct responses
to Slit2 fragments, and these proteins have different growth-promoting cap
acities.