Bansal R, Winkler S, Bheddah S
Departments of Pharmacology and Microbiology and Program in Neurological Sciences, University of Connecticut Medical School, Farmington, Connecticut 06030-3205, USA.
J Neurosci. 1999 Sep 15;19(18):7913-24. doi: 10.1523/JNEUROSCI.19-18-07913.1999.
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 pro-oligodendroblast 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.
半乳糖脑苷脂和硫苷脂是少突胶质细胞质膜和髓鞘的主要半乳糖鞘脂成分，它们在祖细胞停止增殖并开始终末分化的关键时间点首次表达。我们之前发现，一种针对半乳糖脑苷脂/硫苷脂的抗体可阻止终末分化，这表明这些半乳糖脂在少突胶质细胞分化中发挥作用。我们现在研究了少突胶质细胞的分化情况：（1）对其他抗半乳糖脂抗体的反应，结果表明抗硫苷脂O4抗体而非抗半乳糖脑苷脂O1抗体可阻止终末分化，可能是通过模拟内源性配体来实现的；（2）在由于半乳糖鞘脂合成关键酶——神经酰胺半乳糖基转移酶基因突变而无法合成这些脂质的转基因小鼠中进行研究。我们发现，半乳糖基转移酶mRNA表达始于该谱系的晚期祖细胞[前少突胶质母细胞（Pro-OL）]阶段，并且在缺乏半乳糖基转移酶的情况下不会合成晚期祖细胞标志物前少突胶质母细胞抗原。消除这些半乳糖脂的主要结果是，无论是在培养物中还是在体内，终末分化的少突胶质细胞数量都增加了两到三倍。由于在突变培养物中，分化的总体模式以及祖细胞增殖和存活水平似乎未发生改变，我们得出结论，少突胶质细胞数量的增加是由分化速率和分化概率的提高所致。与这两种实验方法一致，我们提出了一个模型，其中半乳糖鞘脂（特别是半乳糖脑苷脂和/或硫苷脂）作为环境信息的传感器和/或传递者，与内源性配体相互作用，作为少突胶质细胞分化的负调节因子，监测Pro-OL向终末分化、产生髓鞘的少突胶质细胞的适时进展。
