Fujita N, Kemper A, Dupree J, Nakayasu H, Bartsch U, Schachner M, Maeda N, Suzuki K, Popko B
Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
J Neurosci. 1998 Mar 15;18(6):1970-8. doi: 10.1523/JNEUROSCI.18-06-01970.1998.
The myelin-associated glycoprotein (MAG) is a member of the immunoglobulin gene superfamily and is thought to play a critical role in the interaction of myelinating glial cells with the axon. Myelin from mutant mice incapable of expressing MAG displays various subtle abnormalities in the CNS and degenerates with age in the peripheral nervous system (PNS). Two distinct isoforms, large MAG (L-MAG) and small MAG (S-MAG), are produced through the alternative splicing of the primary MAG transcript. The cytoplasmic domain of L-MAG contains a unique phosphorylation site and has been shown to associate with the fyn tyrosine kinase. Moreover, L-MAG is expressed abundantly early in the myelination process, possibly indicating an important role in the initial stages of myelination. We have adapted the gene-targeting approach in embryonic stem cells to generate mutant mice that express a truncated form of the L-MAG isoform, eliminating the unique portion of its cytoplasmic domain, but that continue to express S-MAG. Similar to the total MAG knockouts, these animals do not express an overt clinical phenotype. CNS myelin of the L-MAG mutant mice displays most of the pathological abnormalities reported for the total MAG knockouts. In contrast to the null MAG mutants, however, PNS axons and myelin of older L-MAG mutant animals do not degenerate, indicating that S-MAG is sufficient to maintain PNS integrity. These observations demonstrate a differential role of the L-MAG isoform in CNS and PNS myelin.
髓鞘相关糖蛋白（MAG）是免疫球蛋白基因超家族的成员，被认为在髓鞘形成的神经胶质细胞与轴突的相互作用中起关键作用。来自无法表达MAG的突变小鼠的髓鞘在中枢神经系统中表现出各种细微异常，并在周围神经系统（PNS）中随年龄退化。通过初级MAG转录本的可变剪接产生两种不同的异构体，即大MAG（L-MAG）和小MAG（S-MAG）。L-MAG的胞质结构域含有一个独特的磷酸化位点，并且已被证明与fyn酪氨酸激酶相关。此外，L-MAG在髓鞘形成过程的早期大量表达，这可能表明其在髓鞘形成的初始阶段起重要作用。我们采用胚胎干细胞基因靶向方法来生成突变小鼠，这些小鼠表达截短形式的L-MAG异构体，消除其胞质结构域的独特部分，但继续表达S-MAG。与完全敲除MAG的小鼠相似，这些动物没有明显的临床表型。L-MAG突变小鼠的中枢神经系统髓鞘表现出了报道的完全敲除MAG小鼠的大多数病理异常。然而，与MAG基因敲除小鼠不同的是，年龄较大的L-MAG突变动物的周围神经系统轴突和髓鞘不会退化，这表明S-MAG足以维持周围神经系统的完整性。这些观察结果证明了L-MAG异构体在中枢神经系统和周围神经系统髓鞘中的不同作用。
