Neurotrophins support regenerative axon assembly over CSPGs by an ECM-integrin-independent mechanism.
Chondroitin sulfate proteoglycans (CSPGs) and myelin-based inhibitors are the most studied inhibitory molecules in the adult central nervous system. Unlike myelin-based inhibitors, few studies have reported ways to overcome the inhibitory effect of CSPGs. Here, by using regenerating adult dorsal root ganglion (DRG) neurons, we show that chondroitin sulfate proteoglycans inhibit axon assembly by a different mechanism from myelin-based inhibitors. Furthermore, we show that neither Rho inhibition nor cAMP elevation rescues extracellular factor-induced axon assembly inhibited by CSPGs. Instead, our data suggest that CSPGs block axon assembly by interfering with integrin signaling. Surprisingly, we find that nerve growth factor (NGF) promotes robust axon growth of regenerating DRG neurons over CSPGs. We have found that, unlike naive neurons that require simultaneous activation of neurotrophin and integrin pathways for axon assembly, either neurotrophin or integrin signaling alone is sufficient to induce axon assembly of regenerating neurons. Thus, our results suggest that the ability of NGF to overcome CSPG inhibition in regenerating neurons is probably due to the ability of regenerating neurons to assemble axons using an integrin-independent pathway. Finally, our data show that the GSK-3beta-APC pathway, previously shown to mediate developing axon growth, is also necessary for axon regeneration.
Zhou
Feng-Quan
FQ
Neuroscience Center, 8109 Neuroscience Research Building, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Walzer
Mark
M
Wu
Yao-Hong
YH
Zhou
Jiang
J
Dedhar
Shoukat
S
Snider
William D
WD
D053674:Aggrecans; D000818:Animals; D001369:Axons / Q000378:metabolism*; D002478:Cells, Cultured; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism* / Q000494:pharmacology; D005109:Extracellular Matrix / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects; D016023:Integrins / Q000502:physiology*; D037181:Lectins, C-Type; D051379:Mice; D008954:Models, Biological; D009185:Myelin Proteins / Q000494:pharmacology; D020932:Nerve Growth Factor / Q000037:antagonists & inhibitors; D009414:Nerve Growth Factors / Q000502:physiology*; D009416:Nerve Regeneration / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D000070798:Nogo Proteins; D012183:Retrograde Degeneration / Q000534:rehabilitation; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors
C508320:Acan protein, mouse; D053674:Aggrecans; D011508:Chondroitin Sulfate Proteoglycans; D016326:Extracellular Matrix Proteins; D016023:Integrins; D037181:Lectins, C-Type; D009185:Myelin Proteins; D009414:Nerve Growth Factors; D000070798:Nogo Proteins; C000603201:Rtn4 protein, mouse; D020932:Nerve Growth Factor; D020741:rho GTP-Binding Proteins