Canine distemper virus (CDV) induces oligodendroglial degeneration and multifocal demyelination in the central nervous system. The mechanism of oligodendrocyte degeneration is not understood but it has been shown that there is a restricted infection of these cells without viral protein production. Using a combination of immunocytochemistry and in situ hybridization we were able to demonstrate the transcription of the entire virus genome throughout the whole observation period (7-35 days after infection) in oligodendrocytes in CDV-infected brain cell cultures. Therefore, the lack of viral protein and particle production can not be explained on the basis of a defective viral transcription. The present study also shows that a restricted infection of oligodendrocytes with CDV down-regulates the transcription of the major myelin genes coding for proteolipid protein, myelin basic protein (MBP) and myelin-associated glycoprotein in a very similar way. Using densitometry for in situ hybridization products of MBP in populations of normal and infected oligodendrocytes, an effect could be observed long before morphological changes were detectable. The present results strongly suggest that demyelination in distemper is induced by a restricted CDV infection of oligodendrocytes which down-regulates the expression of a variety of cellular genes, in particular those coding for myelin proteins. Consequently, the infected cells are no longer able to synthesize all the membrane compounds which are necessary for maintaining their structural integrity.