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

Abstract

Myelin-associated glycoprotein (MAG) has been implicated in inhibition of nerve regeneration in the CNS. This results from interactions between MAG and the Nogo receptor and gangliosides on the apposing axon, which generates intracellular inhibitory signals in the neuron. However, because myelin-axon signaling is bidirectional, we undertook an analysis of potential MAG-activated signaling in oligodendrocytes (OLs). In this study, we show that antibody cross-linking of MAG on the surface of OLs (to mimic axonal binding) leads to the redistribution of MAG into detergent (TX-100)-insoluble complexes, hyperphosphorylation of Fyn, dephosphorylation of serine and threonine residues in specific proteins, including lactate dehydrogenase and the β subunit of the trimeric G-protein-complex, and cleavage of α-fodrin followed by a transient depolymerization of actin. We propose that these changes are part of a signaling cascade in OLs associated with MAG function as a mediator of axon-glial communication which might have implications for the mutual regulation of the formation and stability of axons and myelin.

The Inhibition Site on Myelin-Associated Glycoprotein Is within Ig-Domain 5 and Is Distinct from the Sialic Acid Binding Site

“…This is also consistent with gangliosides potentiating, but not being necessary for inhibition by MAG. Our conclusion is that gangliosides increase the clustering of the receptor-ligand complexes, most likely as others have reported, in lipid rafts (Vinson et al, 2003;Marta et al, 2004). In addition, because the binding of MAG to NgR2 is reported to be sialic acid-dependent, it is possible that the inhibition by MAG is also potentiated through this interaction (Venkatesh et al, 2005).…”

Quaking I controls a unique cytoplasmic pathway that regulates alternative splicing of myelin-associated glycoprotein

“…As shown in Fig. 3F, QKI deficiency in qk v /qk v mutant OLs caused a shift of the hnRNPA1 mRNA from translationally dormant mRNPs (fraction 2) into initiating 80S ribosome (fraction 3) and translating polyribosomes (fractions [4][5][6][7][8][9][10]. This experiment suggests that deficiency of cytoplasmic QKIs results in abnormally enhanced translational initiation of the hnRNPA1 mRNA in the myelinating brain.…”

Rafts in oligodendrocytes: Evidence and structure–function relationship

“…The latter are required for transmitting MAG-mediated signals into neurons. Interestingly, in primary OLGs, antibody-induced cross-linking of MAG causes the (re-)partitioning of the protein from a soluble into a DRM fraction (Marta et al, 2004). Cross-linking apparently seems to induce recruitment into rafts and the observed clustering thus results from the cross-linking as such rather than from the coalescence of individual, MAG containing rafts.…”