Schwann cell-derived factor-induced modulation of the NgR/p75NTR/EGFR axis disinhibits axon growth through CNS myelin in vivo and in vitro.
When associated with the Nogo receptor (NgR), the transmembrane receptor p75NTR signals growth cone collapse. Arrest of CNS axon growth in vivo is mediated by CNS myelin-derived inhibitory ligands through either an unknown pathway after NgR- and Ca2+-dependent activation of the epidermal growth factor receptor (EGFR), and/or sequential Rho-A/ROCK/LIM-kinase/cofilin phosphorylation leading to actin depolymerization. Paradoxically, rat retinal ganglion cell (RGC) axons regenerate through the CNS myelin-rich transected optic nerve after intravitreal sciatic nerve grafting without inhibitory ligand neutralization. Here, we show that optic nerve regeneration in vivo correlates with Schwann cell-derived factor-induced cleavage of NgR and Nogo-A, and inactivation of p75NTR signalling by the induction of regulated intramembranous proteolysis (RIP) and the release of both extracellular (p75ECD) and intracellular (p75ICD) domains. Hence, Schwann cell-derived factors compromise inhibitory signalling by (i) antagonizing ligand/NgR binding with metalloproteinase-cleaved Nogo-A peptides; (ii) RIP of p75NTR; (iii) competitively blocking NgR/p75NTR clustering with soluble p75ECD; and (iv) consequent reduced downstream EGFR phosphorylation and suppression of Rho-A activation. Moreover, in RGC cultures, exogenous tumour necrosis- converting enzyme (TACE) initiates RIP of p75NTR, reduces EGFR phosphorylation, suppresses activation of Rho-A, cleaves the ECD from both NgR and TROY, and disinhibits neurotrophic factor (NTF) stimulated RGC neurite outgrowth in the presence of CNS myelin. Soluble NgRECD binds all CNS myelin-derived ligands and thus has the potential to act as an inhibitory signalling antagonist, but the role of TROY and its shed ectodomain in growth cone mobility is unknown. siRNA knockdown of p75NTR also inactivates Rho-A and disinhibits NTF-stimulated RGC neurite outgrowth in cultures with added CNS myelin. In all the above experimental paradigms, Schwann cell-derived factor/NTF-induced attenuation of NgR/p75NTR signalling suppresses EGFR activation, thereby potentiating axon growth disinhibition.
Ahmed
Zubair
Z
Molecular Neuroscience Group, Division of Medical Sciences, University of Birmingham, Birmingham, UK.
Suggate
Ellen L
EL
Brown
Elspeth R
ER
Dent
Russell G
RG
Armstrong
Stephanie J
SJ
Barrett
Lee B
LB
Berry
Martin
M
Logan
Ann
A
D051722:ADAM Proteins / Q000378:metabolism / Q000494:pharmacology; D000072198:ADAM17 Protein; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology; D001369:Axons / Q000502:physiology*; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000502:physiology; D005260:Female; D019922:GAP-43 Protein / Q000502:physiology; D058851:GPI-Linked Proteins; D009185:Myelin Proteins; D009186:Myelin Sheath / Q000502:physiology*; D009414:Nerve Growth Factors / Q000494:pharmacology; D009416:Nerve Regeneration / Q000502:physiology*; D000070816:Nogo Receptor 1; D009900:Optic Nerve / Q000502:physiology; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide / Q000502:physiology; D012165:Retinal Ganglion Cells / Q000502:physiology; D012583:Schwann Cells / Q000502:physiology*; D015854:Up-Regulation
D051017:Apoptosis Regulatory Proteins; C485843:Bex3 protein, rat; D019922:GAP-43 Protein; D058851:GPI-Linked Proteins; D009185:Myelin Proteins; D009414:Nerve Growth Factors; D000070816:Nogo Receptor 1; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide; C486581:Rtn4r protein, rat; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat