Developmental Cell, October 2017
Anissa Kempf, 1,6,9 Enrica Boda, 2 Jessica C.F. Kwok, 3,8 Rafael Fritz, 4 Valentina Grande, 2 Andrea M. Kaelin, 1 Zorica Ristic, 1 Andre Schmandke, 1 Antonio Schmandke, 1 Bjoern Tews, 5 James W. Fawcett, 3 Olivier Pertz, 4,7 Annalisa Buffo, 2 and Martin E. Schwab 1
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.
In this picture young neurons (in red) produced by neural stem cells migrate away from the mother cells.
In a first migratory phase, young neurons slide over each other thanks to repulsive signals mediated by the interaction between NoGo-A and Heparan Sulphate Proteoglycans locate on the cells' membrane.
NoGo-A is a membrane protein. Its tail (delta20 segment, in purple) interacts with Heparan Sulphate Proteoglycans (light blue) on the membrane of adjacent cells, thereby inducing diverse effects on brain plasticity.
Brain Research Institute, University of Zurich and Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, 8057 Zurich, Switzerland
Department of Neuroscience, Neuroscience Institute Cavalieri Ottolenghi (NICO), Università degli Studi di Torino, Orbassano, Turin 10043, Italy
John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Robinson Way, Cambridge CB2 0PY, UK
Institute for Biochemistry and Genetics, Department of Biomedicine, University of Basel, 4058 Basel, Switzerland
Schaller Research Group at the University of Heidelberg and the German Cancer Research Center (DKFZ), Molecular Mechanisms of Tumor Invasion, 69120 Heidelberg, Germany
Present address: University of Oxford, Centre for Neural Circuits and Behaviour, Oxford OX1 3SR, UK
Present address: Institute of Cell Biology, University of Bern, Bern 3012, Switzerland
Present address: School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK
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