Gangliosides are functional nerve cell ligands for myelin-associated glycoprotein (MAG), an inhibitor of nerve regeneration

Abstract

Myelin-associated glycoprotein (MAG) binds to the nerve cell surface and inhibits nerve regeneration. The nerve cell surface ligand(s) for MAG are not established, although sialic acid-bearing glycans have been implicated. We identify the nerve cell surface gangliosides GD1a and GT1b as specific functional ligands for MAG-mediated inhibition of neurite outgrowth from primary rat cerebellar granule neurons. MAG-mediated neurite outgrowth inhibition is attenuated by (i) neuraminidase treatment of the neurons; (ii) blocking neuronal ganglioside biosynthesis; (iii) genetically modifying the terminal structures of nerve cell surface gangliosides; and (iv) adding highly specific IgG-class antiganglioside mAbs. Furthermore, neurite outgrowth inhibition is mimicked by highly multivalent clustering of GD1a or GT1b by using precomplexed antiganglioside Abs. These data implicate the nerve cell surface gangliosides GD1a and GT1b as functional MAG ligands and suggest that the first step in MAG inhibition is multivalent ganglioside clustering.

Interruption of ganglioside synthesis produces central nervous system degeneration and altered axon–glial interactions

“…Neuronal gangliosides mediate communication between axons and myelin-producing cells (23)(24)(25). MAG, a myelin-associated protein found on the myelin membrane adjacent to the axon, interacts with neuronal gangliosides to stabilize axonal-myelin interactions.…”

Rafts in oligodendrocytes: Evidence and structure–function relationship

“…It is a sialic acid-binding protein of the siglec (sialic acid-dependent immunoglobulin-like family member lectin) family. MAG is restricted to the periaxonal membrane of the myelin sheath where it interacts with molecules on the axonal membrane, including the gangliosides GD1a and GT1b (Vinson et al, 2001;Vyas et al, 2002) and the GPI-linked Nogo receptor (NgR) (Domeniconi et al, 2002;Fournier et al, 2001;Liu et al, 2002). As the affinity of a monomeric siglec molecule (e.g.…”

Myelin associated glycoprotein cross-linking triggers its partitioning into lipid rafts, specific signaling events and cytoskeletal rearrangements in oligodendrocytes

“…Although this might be important in the regulation of unwanted nerve sprouting in the mature nervous system, it severely limits neuron recovery after injury. Myelin associated glycoprotein (MAG), a sialic acid-binding protein on the periaxonal myelin membrane, is implicated in the inhibition of nerve regeneration (Vyas and Schnaar, 2001;Weiss et al, 2001;Spencer et al, 2003) through its interaction with molecules on axonal plasma membranes, such as microtubule-associated protein 1B (Franzen et al, 2001), gangliosides GD1a and GT1b (Kelm et al, 1994;Crocker et al, 1996;Vinson et al, 2001;Vyas et al, 2002), and the recently discovered glycosylphosphatidylinositol (GPI)-linked Nogo receptor (neuronal receptor for Nogo, another myelin inhibitor of axonal regeneration) (Fournier et al, 2001;Domeniconi et al, 2002;Liu et al, 2002). Binding of an extracellular domain of MAG to apposing molecules on the axonal surface generates an inhibitory signal in the neuron that involves p75, RhoA and Rac1 signaling (Niederost et al, 2002;Wang et al, 2002).…”