Multipotent hematopoietic progenitor cell lines (FDCP-Mix) infected with a retroviral vector expressing the GM-CSF gene show functional downregulation of the GM-CSF receptor when maintained in IL-3 and activation of the receptor resulting in synchronous differentiation into mature granulocytes and macrophages on withdrawal of IL-3. This system has now been used to investigate whether or not receptors for some of the other growth factors are also influenced as a consequence of differentiation. We show here the lineage specific receptors for M-CSF, G-CSF and erythropoietin are all upregulated, regardless of whether or not differentiation is induced by GM-CSF or by other conditions. Concomitant induction of the mRNA coding for the ligands M-CSF and G-CSF, but not for erythropoietin, suggests that M-CSF and possibly G-CSF facilitate macrophage or granulocyte differentiation by an autocrine stimulation of the lineage specific receptors. FDCP-Mix mutants that are blocked in their ability to differentiate on exposure to GM-CSF, but that still require GM-CSF for proliferation, do not express increased levels of M-CSF receptor nor M-CSF. Based on these data, we suggest that expression of these lineage specific receptors is part of the intrinsic endogenous program of myeloid differentiation.