We have studied the transcription factors SCIP and Krox-20 in differentiating Schwann cells-during normal development, in experimentally induced degenerating and regenerating peripheral nerves, and in cell culture-and have compared the expression of these regulators to a battery of genes that mark distinct stages in Schwann cell differentiation. In the myelinating Schwann cell lineage, we find that SCIP is initially induced by contact with axons and first appears near the last round of cell division in immature cells. This expression is transient--it is maximal in "promyelinating" cells and is then extinguished as Schwann cells overtly differentiate and myelinate axons. In contrast, Krox-20 appears in cells 24-36 h after they become SCIP+ and continues to be expressed in mature myelinating cells. These differences in regulation are seen in normal development, in regenerating nerves following nerve crush, and in cultured Schwann cells stimulated to adopt a myelination phenotype by elevation of intracellular cyclic AMP. Importantly, transient SCIP expression is also observed in the nonmyelinating Schwann cell lineage, but Krox-20 expression is not. Together with the myelination phenotypes exhibited by SCIP and Krox-20 mutant mice, these results suggest that SCIP preferentially acts during the predifferentiated phases of Schwann cell development, while in contrast, Krox-20 is associated with the later commitment to myelination and may therefore function as a direct transactivator of myelination genes.