Negative Regulation of Oligodendrocyte Differentiation by Galactosphingolipids

Abstract

Galactocerebroside and sulfatide, major galactosphingolipid components of oligodendrocyte plasma membranes and myelin, are first expressed at a critical point, when progenitors cease to proliferate and commence terminal differentiation. We showed previously that an antibody to galactocerebroside/ sulfatide arrested terminal differentiation, suggesting a role for these galactolipids in oligodendrocyte differentiation. We have now investigated the differentiation of oligodendrocytes (1) in response to other anti-galactolipid antibodies, showing that anti-sulfatide O4 but not anti-galactocerebroside O1 blocks terminal differentiation, perhaps by mimicking an endogenous ligand, and (2) in a transgenic mouse unable to synthesize these lipids because of mutation of the gene for ceramide galactosyltransferase, a key enzyme for galactosphingolipid synthesis. We find that galactosyltransferase mRNA expression begins at the late progenitor [pro-oligodendroblast (Pro-OL)] stage of the lineage and that the late progenitor marker prooligodendroblast antigen is not synthesized in the absence of galactosyltransferase. The principal outcome of the elimination of these galactolipids is a two-to threefold enhancement in the number of terminally differentiated oligodendrocytes both in culture and in vivo. Because the general pattern of differentiation and the level of progenitor proliferation and survival appear to be unaltered in the mutant cultures, we conclude that the increased number of oligodendrocytes is caused by an increased rate and probability of differentiation. In agreement with these two experimental approaches, we present a model in which galactosphingolipids (in particular galactocerebroside and/or sulfatide) act as sensors and/or transmitters of environmental information, interacting with endogenous ligands to function as negative regulators of oligodendrocyte differentiation, monitoring the timely progress of Pro-OLs into terminally differentiating, myelin-producing oligodendrocytes.

Paranodal junction formation and spermatogenesis require sulfoglycolipids

“…Indeed, oligodendrocyte differentiation is enhanced in CGTknockout mice in vitro and in vivo, indicating that GalCer and͞or sulfatide act as negative regulators of the entry of oligodendrocytes into terminal differentiation (28). Furthermore, the terminal differentiation was blocked by anti-sulfatide antibody O4 but not by anti-GalCer antibody O1 (28). These findings strongly suggest that sulfatide is a key regulator of the oligodendrocyte differentiation.…”

“…This fact leads to the prediction that these lipids play a role in the regulation of oligodendrocyte differentiation, in addition to their eventual roles as structural components of mature myelin. Indeed, oligodendrocyte differentiation is enhanced in CGTknockout mice in vitro and in vivo, indicating that GalCer and͞or sulfatide act as negative regulators of the entry of oligodendrocytes into terminal differentiation (28). Furthermore, the terminal differentiation was blocked by anti-sulfatide antibody O4 but not by anti-GalCer antibody O1 (28).…”

Oligodendroglial Progenitor Cell Therapy Limits Central Neurological Deficits in Mice with Metachromatic Leukodystrophy

“…Furthermore, it is unclear whether the accumulation of sulfatides in perinatal OLPs in the MLD mouse model, which might still be at a low concentration at the time of the transplantation, has an impact on their survival and/or differentiation. Some recent work elegantly illustrates the role of sphingolipids during oligodendroglial differentiation (Bansal et al, 1999;Hirahara et al, 2004;Yaghootfam et al, 2005). For example, absence of sulfatides stimulates a premature differentiation of OLPs.…”

Dysfunction of Platelet-derived Growth Factor Receptor α (PDGFRα) Represses the Production of Oligodendrocytes from Arylsulfatase A-deficient Multipotential Neural Precursor Cells

“…Various studies have shown that OL differentiation could either be promoted by a deficient synthesis of sulfatides (56,57) or inhibited by anti-sulfatide antibodies (58,59), suggesting that sulfatides negatively regulate OL differentiation (20,21). However, the mechanism of this repression has remained unaddressed.…”

“…One interpretation from these results is that sulfatides might repress the sensitivity of OPCs to proliferating signals such as PDGF-AA, thereby reducing the pool of progenitors available for differentiation into mature OLs. Sulfatides are crucial sphingolipids in myelin architecture (19) and have been found to negatively regulate the maturation of OPCs into differentiated OLs (20,21), but the mechanism is still unknown. Sphingolipids, including sulfatides, have structural and functional roles in DRMs (22,23) and participate in caveolar and exosomal biogenesis (22, 24 -26).…”