Sensory Axon Response to Substrate-Bound Slit2 Is Modulated by Laminin and Cyclic GMP

In vertebrates, Slit2 is a chemorepellent for some developing axons but stimulates 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 fragments, 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 to substrate-bound Slit2 fragments in the stripe assay. Slit2 fragments were avoided by DRG axons when expressed on membranes or coated as stripes on laminin. However, when the Slit2 stripes were coated on fibronectin, DRG axons 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 laminin-1 peptide. These results strongly support the idea that extracellular matrix proteins modulate the response of growth cones to chemotropic molecules by modulating cyclic nucleotide levels.