The role of Nogo-receptor and gangliosides in myelin-associated glycoprotein-mediated axonal regeneration and protection.

摘要

Myelin-associated glycoprotein (MAG) is a key signaling protein located at the interface between myelin sheets and axons. MAG has been shown to bind axonal receptors, gangliosides (GD1a and GT1b) and glycosylphosphatidylinositol (GPI)-anchored Nogo receptors (NgRs), to mediate various biological functions. In the injured nervous system, MAG on residual myelin binds to receptors on axons, inhibits axon outgrowth and limits functional recovery, yet MAG also plays a key role in maintaining axon-myelin stability. Conflicting reports identify gangliosides and NgRs as exclusive axonal receptors for MAG.;We used different pharmacological agents to distinguish the relative roles of gangliosides and NgRs in MAG-mediated inhibition of neurite outgrowth from three nerve cell types, dorsal root ganglion neurons (DRGN), cerebellar granule neurons (CGN), and hippocampal neurons (HN). Primary rat neurons were cultured on control substrata and substrata adsorbed with full length native MAG extracted from purified myelin. The receptors responsible for MAG inhibition of neurite outgrowth varied with nerve cell type. In DRGN, the majority of MAG inhibition was via NgRs, but there was a smaller percentage of inhibition that was via gangliosides. In contrast to DRGN, in CGN MAG inhibition was exclusively via gangliosides, whereas inhibition of HN outgrowth was mostly through gangliosides and only a modest portion of the inhibition was mediated by NgRs. Our data indicate that the axonal receptor used in MAG-mediated inhibition is nerve cell type dependent.;When the Mag gene is disrupted, animals appear normal at birth but experience progressive axon degeneration into adulthood. We cultured postnatal rat DRGN on control surfaces and surfaces adsorbed with full-length native MAG from purified myelin and treated with vincristine sulfate salt (VIN) to induce neurite toxicity. DRGN plated on control surfaces revealed significant neurite toxicity, whereas neurites on MAG coated surfaces were protected. When we examined the role of NgR and gangliosides in MAG-mediated neurite protection we found that protection involved gangliosides and not Nogo receptors. In conclusion, the same nerve cell type uses different MAG receptors to mediate different biological functions, neurite outgrowth inhibition and protection.