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

Publication date: Available online 21 September 2017
Source:Developmental Cell
Author(s): Anissa Kempf, Enrica Boda, Jessica C.F. Kwok, Rafael Fritz, Valentina Grande, Andrea M. Kaelin, Zorica Ristic, Andre Schmandke, Antonio Schmandke, Bjoern Tews, James W. Fawcett, Olivier Pertz, Annalisa Buffo, Martin E. Schwab
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.

Graphical abstract

Teaser

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.


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