Negative regulation of oligodendrocyte differentiation by galactosphingolipids

Galactocerebroside and sulfatide, major galactosphingolipid components of o ligodendrocyte plasma membranes and myelin, are first expressed at a critic al point, when progenitors cease to proliferate and commence terminal diffe rentiation. We showed previously that an antibody to galactocerebroside/sul fatide arrested terminal differentiation, suggesting a role for these galac tolipids in oligodendrocyte differentiation. We have now investigated the d ifferentiation of oligodendrocytes (1) in response to other anti-galactolip id antibodies, showing that anti-sulfatide O4 but not anti-galactocerebrosi de O1 blocks terminal differentiation, perhaps by mimicking an endogenous l igand, and (2) in a transgenic mouse unable to synthesize these lipids beca use of mutation of the gene for ceramide galactosyltransferase, a key enzym e for galactosphingolipid synthesis. We find that galactosyltransferase mRN A expression begins at the late progenitor [pro-oligodendroblast (Pro-OL)] stage of the lineage and that the late progenitor marker prooligodendroblas t antigen is not synthesized in the absence of galactosyltransferase. The p rincipal outcome of the elimination of these galactolipids is a two- to thr eefold enhancement in the number of terminally differentiated oligodendrocy tes both in culture and in vivo. Because the general pattern of differentia tion and the level of progenitor proliferation and survival appear to be un altered in the mutant cultures, we conclude that the increased number of ol igodendrocytes is caused by an increased rate and probability of differenti ation. In agreement with these two experimental approaches, we present a mo del 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.