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Something you need to know about GM1 Gangliosides as receptors in axon-myelin interactions The evolution of bacterial toxins that specifically bind to brain GM1 gangliosides suggested that endogenous vertebrate lectins may have evolved to do the same. A search for GM1 ganglioside binding proteins in the brain led to myelin-associated glycoprotein (MAG), and to an enhanced understanding of GM1 ganglioside functions in axon-myelin interactions. MAG is a single-pass transmembrane protein that is selectively expressed by myelinating cells: oligodendrocytes in the CNS and Schwann cells in the PNS. In the CNS, MAG is found only on the innermost (periaxonal) wrap of myelin, directly apposed to the axon surface. In the PNS it is also found on periaxonal myelin, as well as on Schmidt-Lanterman incisures, lateral loops, and the inner and outer mesaxons . Based on its expression, MAG was long proposed to be involved in axon-myelin interactions. Although gene deletion of MAG in mice did not result in severe demyelination as some had expected , the study of Mag-null mice reveals important roles for MAG in axon-myelin interactions relating to axon cytoarchitecture, axon stability, and axon regeneration. Mag-null mice myelinate axons throughout the nervous system, and most myelin in Mag-null mice appears grossly normal. However, myelination is delayed, and there is a higher proportion of myelin structural abnormalities. Mag-null mice also have increased numbers of poorly formed nodes of Ranvier and disruption of the spatial patterns of nodal ion channels and adhesion molecules. Normally, myelination induces local increases in neurofilament phosphorylation in ensheathed axons, resulting in increased axon diameter and increased conduction velocity. Mag-null mice display reduced neurofilament phosphorylation and spacing and reduced axon diameter, even in myelinated axons . Myelination also nurtures axons; dysmyelination results in axon degeneration. MAG 1
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is part of this nurturing effect in that Mag-null mice display axon degeneration in both central and peripheral nerves, resulting in progressive axonal loss over their lifetimes . Notably, MAG also protects axons from short-term toxic insults; Mag-null mice are more sensitive to axonopathic neurotoxins, and soluble forms of MAG can protect axons from neurotoxic insults. In addition to its broad role in supporting healthy longand short-term axon-myelin interactions, MAG also inhibits axon regeneration . MAG is one of a suite of molecules, including those on residual myelin, that limit recovery from traumatic nervous system injury by signaling axons to halt outgrowth . Although genetic deletion of these factors has, thus far, failed to generate broad and robust regeneration after CNS injury, Mag-null mice display increased axon sprouting after injury in some studies. From long-term axon-myelin stabilization to inhibition of regeneration, all of the physiological roles of MAG have, at least in part, been linked to its recognition of brain GM1gangliosides.
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