Abstract: Antisilencer or antirepressor elements have been described, thus far, for only a few eukaryotic genes and were identified by their ability not to augment gene expression per se but to override repression mediated via negative transcription regulatory elements. Here we report the first case of antisilencing for a neural-specific gene, the myelin proteolipid protein (PLP) gene (Plp). PLP is the most abundant protein found in CNS myelin. The protein is synthesized in oligodendrocytes, and its expression is regulated developmentally. Previously we have shown that a PLP-lacZ transgene (which includes the entire sequence for Plp intron 1) is regulated in mice, in a manner consistent with the spatial and temporal expression of the endogenous Plp gene. In the present report, we demonstrate by transfection analyses, using various PLP-lacZ deletion constructs, that Plp intron 1 DNA contains multiple elements that collectively regulate Plp gene expression in oligodendrocytes. One of these regulatory elements functions as an antisilencer element, which acts to override repression mediated by at least two negative regulatory elements located elsewhere within Plp intron 1 DNA. The mechanism for antisilencing appears to be complex as the intragenic region that mediates this function binds multiple nuclear factors specifically.