Sensory axon response to substrate-bound Slit2 is modulated by laminin andcyclic GMP

In vertebrates, Slit2 is a chemorepellent for some developing axons but sti mulates axonal elongation and branching of sensory axons. In vivo, Slit2 is cleaved into 140-kDa N-terminal (Slit2-N) and 55- to 60-kDa C-terminal fra gments, but the uncleaved/full-length form can also be isolated from brain extracts. As Slit2-N and full-length Slit2 bind tightly to cell membranes, we decided to explore the response of rat dorsal root ganglia (DRG) axons t o substrate-bound Slit2 fragments in the stripe assay. Slit2 fragments were avoided by DRG axons when expressed on membranes or coated as stripes on l aminin. However, when the Slit2 stripes were coated on fibronectin, DRG axo ns still avoided full-length Slit2 but grew preferentially on Slit2-N. DRG axon response to Slit2 fragments could be modulated by cGMP and by a lamini n-l peptide. These results strongly support the idea that extracellular mat rix proteins modulate the response of growth cones to chemotropic molecules by modulating cyclic nucleotide levels.