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

• Published in: Developmental cell 2017-10, Vol.43 (1), p.24-34.e5
• Main Authors: Kempf, Anissa, Boda, Enrica, Kwok, Jessica C.F., Fritz, Rafael, Grande, Valentina, Kaelin, Andrea M., Ristic, Zorica, Schmandke, Andre, Schmandke, Antonio, Tews, Bjoern, Fawcett, James W., Pertz, Olivier, Buffo, Annalisa, Schwab, Martin E.
• Format: Article
• Language: English
• Subjects: adhesion; Animals; Carrier Proteins - metabolism; Cell Line; Cell Movement - physiology; Cell Shape - physiology; Cells, Cultured; Heparan Sulfate Proteoglycans - metabolism; Heparitin Sulfate - metabolism; HSPG; Mice; migration; Neurites - metabolism; neuroblast; Neuronal Outgrowth - physiology; Nogo Proteins - metabolism; nogo-A; outgrowth; Protein Binding; Proteoglycans - metabolism; Receptors, Lysosphingolipid - metabolism; RMS; spreading; SVZ; syndecan
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2017.08.014

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. [Display omitted] •Nogo-A-Δ20 inhibits cell spreading and neurite outgrowth via HSPGs•Nogo-A-Δ20 binds HSPGs and activates RhoA via HSPGs•The HSPG family members Sdc3 and Sdc4 are required for Nogo-A-Δ20 inhibition•Nogo-A-Δ20 regulates neuroblast migration via HSPGs but independently of 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.