The c-kit proto-oncogene product is a major regulator of early hematopoiesis in mice. We show here that the avian c-Kit protein, together with the c-erbB protooncogene product, regulates self-renewal and differentiation in two types of normal chick erythroid progenitors. A relatively frequent progenitor expressing only c-Kit transiently proliferated in response to avian c-Kit ligand (stem cell factor [SCF]). A second, rare progenitor coexpressed c-Kit and c-ErbB and was induced to long-term self-renewal by SCF or transforming growth factor alpha (TGF alpha), a c-ErbB ligand. In the absence of SFC or TGF alpha, both progenitors underwent erythropoietin (Epo)-dependent terminal differentiation with indistinguishable kinetics. Interestingly, Epo induced differentiation in the SCF progenitors even when SCF was present. In contrast, the c-ErbB-expressing, TGF alpha-induced progenitors continued to self-renew when treated with Epo plus the growth factors SCF, TGF alpha, or both. Expression of c-ErbB thus may be a dominant determinant for the sustained self-renewal of committed erythroid progenitors.