Myelin-associated glycoprotein (Siglec-4) expression is progressively and selectively decreased in the brains of mice lacking complex gangliosides

Abstract

Myelin-associated glycoprotein (MAG, Siglec-4) is a quantitatively minor membrane component expressed preferentially on the innermost myelin wrap, adjacent to the axon. It stabilizes myelin-axon interactions by binding to complementary ligands on the axolemma. MAG, a member of the Siglec family of sialic acid-binding lectins, binds specifically to gangliosides GD1a and GT1b, which are the major sialoglycoconjugates on mammalian axons. Mice with a disrupted Galgt1 gene lack UDP-GalNAc:GM3/GD3 N-acetylgalactosaminyltransferase (GM2/GD2 synthase) and fail to express complex brain gangliosides, including GD1a and GT1b, instead expressing a comparable amount of the simpler gangliosides GM3, GD3, and O-acetyl-GD3. Galgt1-null mice produce similar amounts of total myelin compared to wild-type mice, but as the mice age, they exhibit axon degeneration and dysmyelination with accompanying motor behavioral deficits. Here we report that Galgt1-null mice display progressive and selective loss of MAG from the brain. At 1.5 months of age, MAG expression was similar in Galgt1-null and wild-type mice. However, by 6 months of age MAG was decreased approximately 60% and at 12 months of age approximately 70% in Galgt1-null mice compared to wild-type littermates. Expression of the major myelin proteins (myelin basic protein and proteolipid protein) was not reduced in Galgt1-null mice compared to wild type. MAG mRNA expression was the same in 12-month-old Galgt1-null compared to wild-type mice, an age at which MAG protein expression was markedly reduced. We conclude that the maintenance of MAG protein levels depends on the presence of complex gangliosides, perhaps due to enhanced stability when MAG on myelin binds to its complementary ligands, GD1a and GT1b, on the apposing axon surface.

Ablation of Neuronal Ceramide Synthase 1 in Mice Decreases Ganglioside Levels and Expression of Myelin-associated Glycoprotein in Oligodendrocytes

“…There appears to be no change in the myelin sheaths because the level of myelin basic protein was very similar in wild type and homozygous CerS1 Ϫ/Ϫ mice. A similar effect has been noticed before, but its origin was different: mice deficient for N-acetylgalactosaminyltransferase show an age-dependent decrease in MAG protein (50). MAG mRNA levels in these mice were unaffected, indicating decreased stability of the MAG protein in the absence of its ganglioside ligands.…”

In vivo metabolic labeling of sialoglycans in the mouse brain by using a liposome-assisted bioorthogonal reporter strategy

“…Isotopic labeling enables pulse−chase experiments but suffers from limited spatial resolution. Alternatively, histological analysis can be performed using lectins (40) and antibodies (41) to provide spatial information on sialoglycans at the static state. The LABOR method allows for spatiotemporal visualization of the dynamic sialylation.…”

The Nogo-66 Receptor Homolog NgR2 Is a Sialic Acid-Dependent Receptor Selective for Myelin-Associated Glycoprotein

“…Growing evidence suggests that MAG is a bifunctional molecule that, with binding to neuronal cell surface ligands, signals to oligodendrocytes (Umemori et al, 1994;Sun et al, 2004). It will be interesting to explore whether NgR1 and NgR2, in addition to their function as MAG/myelin receptors, serve as neuronal MAG ligands that contribute to the stability of myelin sheets and their associated axons in vivo.…”