Schwann cell-derived factor-induced modulation of the NgR/p75NTR/EGFR axis disinhibits axon growth through CNS myelin in vivo and in vitro

Brain : a Journal of Neurology
Zubair AhmedAnn Logan

Abstract

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 ...Continue Reading

Citations

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Dec 22, 2010·Child's Nervous System : ChNS : Official Journal of the International Society for Pediatric Neurosurgery·Martin M MortazaviNicholas Theodore
Jun 17, 2011·Cell Death & Disease·Z AhmedA Logan
Mar 21, 2013·Investigative Ophthalmology & Visual Science·Vasanthy VigneswaraZubair Ahmed
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Apr 26, 2019·Investigative Ophthalmology & Visual Science·Adam ThompsonZubair Ahmed
Aug 19, 2020·Cells·Roberta Romano, Cecilia Bucci

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