The development of cells of the oligodendroglial lineage, from immature progenitor to myelinating cells, occurs largely in a neuronal environment, yet little is known about specific interactions between these 2 cell types. We have tested the effects of medium conditioned by cultures of rat cerebral cortical neurons (CCM), cerebellar granule interneurons (GCM), and a dorsal root ganglion derived cell line (NDCM) on cells of the oligodendroglial lineage in culture. Different stages of the lineage were defined using the cell surface antigens GD3, 04, and GalC. CCM and NDCM were mitogenic for the early GD3+/04- oligodendroglial progenitor, whereas GCM was mitogenic for the later GD3+/04+ stage. Neutralising antibodies to PDGF and bFGF were able to eliminate the mitogenic activity of NDCM and GCM, respectively, but did not abolish the mitogenic effect of CCM. We have demonstrated that neurons in primary culture from distinct CNS regions exert different influences on cells of the oligodendroglial lineage, and specifically that cortical neurons release an unknown mitogen for GD3+/04- oligodendroglial progenitors.