The role of neurons on expression of myelin-associated glycoprotein (MAG) in oligodendrocytes and oligodendroglial differentiation was examined. Primary cultures of oligodendrocytes prepared from neonatal mouse brains were co-cultured with neuronal cells derived from embryonal carcinoma P19 cells. The levels of MAG mRNAs following this co-culture were determined by reverse transcription (RT)-PCR. In oligodendrocytes co-cultured in direct contact with P19-derived neurons, the levels of MAG mRNAs, particularly that of the L-type isoform, were markedly higher than those in cultures without any neuronal cells. On the other hand, when the P19-derived neurons were present, but not in direct contact, no significant induction of MAG expression was found, though oligodendrocytes appeared to mature morphologically. The L-MAG expression was also stimulated when just the neuronal cell membrane fraction was added, which implies that there might be some effecter(s) in the cell membrane which are possibly exerting a signal transduction for myelin formation. These results suggest that morphological differentiation and functional maturation of oligodendrocytes are due to independent factors. The former is caused by some humoral factor(s) liberated from neuronal cells, while the latter resulted from cellular contact with neuronal cells.