Control of Cell Shape, Neurite Outgrowth, and Migration by a Nogo-A/HSPG Interaction

Abstract

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 amino acid Nogo-A region, named 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, and 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 the HSPG family members syndecan-3 and syndecan-4 as functional receptors for Nogo-A-Δ20. Finally, we show in explant cultures ex vivo that Nogo-A-Δ20 promotes the migration of neuroblasts via HSPGs but not S1PR2. The extracellular Δ20 domain of Nogo-A is a potent inhibitor of cell adhesion and neurite outgrowth in the adult CNS. Kempf et al. identify HSPGs as functional receptors for Nogo-A-Δ20. Nogo-A-Δ20 binds to HSPGs and regulates RhoA activation, cell spreading, neurite outgrowth, and neuroblast migration via HSPGs.