THE CYTOPLASMIC DOMAIN OF THE LARGE MYELIN-ASSOCIATED GLYCOPROTEIN ISOFORM IS NEEDED FOR PROPER CNS BUT NOT PERIPHERAL NERVOUS-SYSTEM MYELINATION

The myelin-associated glycoprotein (MAG) is a member of the immunoglob ulin gene superfamily and is thought to play a critical role in the in teraction of myelinating glial cells with the axon. Myelin from mutant mice incapable of expressing MAG displays various subtle abnormalitie s 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 tra nscript. The cytoplasmic domain of L-MAG contains a unique phosphoryla tion site and has been shown to associate with the fyn tyrosine kinase . Moreover, L-MAG is expressed abundantly early in the myelination pro cess, possibly indicating an important role in the initial stages of m yelination. We have adapted the gene-targeting approach in embryonic s tem cells to generate mutant mice that express a truncated form of the L-MAG isoform, eliminating the unique portion of its cytoplasmic doma in, but that continue to express S-MAG. Similar to the total MAG knock outs, these animals do not express an overt clinical phenotype. CNS my elin of the L-MAG mutant mice displays most of the pathological abnorm alities reported for the total MAG knockouts. In contrast to the null MAG mutants, however, PNS axons and myelin of older L-MAG mutant anima ls do not degenerate, indicating that S-MAG is sufficient to maintain PNS integrity. These observations demonstrate a differential role of t he L-MAG isoform in CNS and PNS myelin.