Versican V2 and the central inhibitory domain of Nogo-A inhibit neurite growth via p75NTR/NgR-independent pathways that converge at RhoA

• Published in: Molecular and cellular neuroscience 2004-10, Vol.27 (2), p.163-174
• Main Authors: Schweigreiter, Rüdiger, Walmsley, Adrian R., Niederöst, Barbara, Zimmermann, Dieter R., Oertle, Thomas, Casademunt, Elisabeth, Frentzel, Stefan, Dechant, Georg, Mir, Anis, Bandtlow, Christine E.
• Format: Article
• Language: English
• Subjects: Animals; Cattle; Cell Proliferation; Cerebral Cortex - metabolism; Cerebral Cortex - physiology; CHO Cells; Chondroitin Sulfate Proteoglycans - genetics; Chondroitin Sulfate Proteoglycans - physiology; Cricetinae; Growth Inhibitors - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin Proteins - genetics; Myelin Proteins - physiology; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - physiology; Neurites - physiology; Nogo Proteins; Protein Binding - physiology; Rats; Receptor, Nerve Growth Factor; Receptors, Nerve Growth Factor - genetics; Receptors, Nerve Growth Factor - physiology; rhoA GTP-Binding Protein - genetics; rhoA GTP-Binding Protein - physiology; Signal Transduction - physiology; Versicans
• ISSN: 1044-7431; 1095-9327
• DOI: 10.1016/j.mcn.2004.06.004

Myelin is a major obstacle for regenerating nerve fibers of the adult mammalian central nervous system (CNS). Several proteins including Nogo-A, myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp) and the chondroitin-sulfate proteoglycan (CSPG) Versican V2 have been identified as inhibitory components present in CNS myelin. MAG, OMgp as well as the Nogo specific domain Nogo-66 exert their inhibitory activity by binding to a neuronal receptor complex containing the Nogo-66 receptor NgR and the neurotrophin receptor p75NTR. While this suggests a converging role of the p75NTR/NgR receptor complex for myelin-derived neurite growth inhibitors, we show here that NgR/p75NTR is not required for mediating the inhibitory activity of the two myelin components NiG, unlike Nogo-66 a distinct domain of Nogo-A, and Versican V2. Primary neurons derived from a complete null mutant of p75NTR are still sensitive to NiG and Versican V2. In line with this result, neurite growth of p75NTR deficient neurons is still significantly blocked on total bovine CNS myelin. Furthermore, modulation of RhoA and Rac1 in p75NTR−/− neurons persists with NiG and Versican V2. Finally, we demonstrate that neither NiG nor Versican V2 interact with the p75NTR/NgR receptor complex and provide evidence that the binding sites of NiG and Nogo-66 are physically distinct from each other on neural tissue. These results indicate not only the existence of neuronal receptors for myelin inhibitors independent from the p75NTR/NgR receptor complex but also establish Rho GTPases as a common point of signal convergence of diverse myelin-induced regeneration inhibitory pathways.