Endocrine Abstracts

Upon binding of myelin-derived axon growth inhibitory ligands to the Nogo receptor (NgR), a complex is formed with LINGO-1 and the low affinity neurotrophin receptor p75^NTR, which initiates axon growth cone collapse via a Rho-A-mediated pathway. We reasoned that, after tumor necrosis factor-α converting enzyme (TACE) cleavage of p75^NTR, which triggers the initiation of regulated intramembrane proteolysis (RIP), signalling of growth cone collapse by CNS inhibitory ligands would be blocked and neurite outgrowth promoted. FGF2-stimulated dorsal root ganglia neuron (DRGN) neurite outgrowth was blocked in vitro after the addition of a pre-determined concentration of inhibitory CNS myelin extract. After the addition of TACE to DRGN cultures to cleave p75^NTR and NgR, we monitored FGF2-stimulated DRGN neurite outgrowth in the presence of CNS myelin ligands. TACE cleaved the ectodomain of NgR and p75^NTR, blocked the activation of Rho-A and promoted FGF2-stimulated neurite outgrowth in the presence of CNS myelin ligands. We conclude that TACE-induced ectodomain shedding of NgR and RIP of p75^NTR abrogates axon growth inhibitory signalling and provides a mechanism for disinhibiting CNS axon/neurite growth.