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.