Control of cell shape, neurite outgrowth and migration by a novel Nogo-A/HSPG interaction

Heparan sulfate proteoglycans (HSPGs) critically modulate adhesion-, growth- and migration related processes. Here we show that the transmembrane protein Nogo-A inhibits neurite outgrowth and cell spreading in neurons and Nogo-A-responsive cell lines via HSPGs. The extracellular, active, 180 aa Nogo-A region called Nogo-A-Δ20 binds to heparin and brain derived heparan sulfate glycosaminoglycans (GAGs) but not to the closely related chondroitin sulfate GAGs. HSPGs are required for Nogo-A-Δ20-induced inhibition of adhesion, cell spreading, neurite outgrowth as well as for RhoA activation. Surprisingly, we show that Nogo-A-Δ20 can act via HSPGs independently of its receptor Sphingosine-1-Phosphate receptor 2 (S1PR2). We thereby identify a new functional binding receptor for Nogo-A-Δ20 and show that syndecan-3 and syndecan-4 are responsible for Nogo-A-Δ20-induced effects. Finally, we show in explant cultures ex vivo that Nogo-A-Δ20 promotes the migration of neuroblasts via HSPGs but not S1PR2.