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Myelin transcription factor 1 (Myt1) is a zinc finger DNA-binding protein that is expressed in neural progenitors and oligodendrocyte lineage cells. This study examines the role of Myt1 in oligodendrocyte lineage cells by overexpressing putative functional domains, a four-zinc finger DNA-binding region (4FMyt1) or a central protein–protein interaction domain (CDMyt1), without the predicted transcriptional activation domain. In the presence of mitogens, overexpression of 4FMyt1 inhibited proliferation of oligodendrocyte progenitors, but not cell types (astrocytes and NIH3T3 cells) lacking endogenous Myt1. Expression of 4FMyt1 inhibited the differentiation of oligodendrocyte progenitors into oligodendrocytes as assessed by morphology, immunostaining, and myelin gene expression. Progenitor differentiation was similarly inhibited by expression of CDMyt1 but only partially suppressed by overexpression of the intact Myt1. These data indicate that Myt1 may regulate a critical transition point in oligodendrocyte lineage development by modulating oligodendrocyte progenitor proliferation relative to terminal differentiation and up-regulation of myelin gene transcription. [Copyright &y& Elsevier]