The effect of retinoic acid (RA) on the expression of myelin-specific genes, i.e., proteolipid protein (PLP) and myelin-associated glycoprotein (MAG) in rat glioma C6 cells, was analyzed by Northern blot hybridization. RA-treatment increased the steady-state level of the PLP-specific messages within one day after RA administration and the upregulation reached a maximum on the third day. Concomitantly, the expression of MAG-specific messages in the RA-treated C6 cells dropped below the detectability limit. The expression of the PLP gene was directly related to the RA concentration increasing to approximately 44-fold over the control (untreated cells) level at 10(-6) M RA. The stimulatory effect was vitiated by cycloheximide indicating the involvement of intermediate genes in the PLP gene activation. The total cellular RNA content and the level of cyclophilin mRNA was not changed by the RA-treatment. The present data indicate that RA can be a potent modulator of the myelin-specific gene expression. Furthermore, the reciprocal response of PLP versus MAG genes to RA demonstrates that these two genes utilize different regulatory mechanisms.