Erythropoietin receptor / erythropoietin recognition in octodon degus, guinea pig, mouse and man

Erythropoietin (EPO) plays a central role in the regulation of erythropoiesis in mammals by activating the erythropoietin receptor (EPOR). While both EPO and EPOR have been cloned, the binding sites of EPO and EPOR have not been fully clarified. There is welldocumented biological crossreactivity between human (h), rat and murine (m) EPOs from historical bioassays on polycythemic mice and starved or hypophysectomized rats. However, polycythemic mice did not respond to guinea pig (gp) hypoxic plasma which stimulated erythropoiesis in polycythemic gp (Necas et al. 1976). These observations are extended in the present study which utilizes erythroid BFU-E colony cultures of 4 species: h, m, gp, and octodon degus (od). Hypoxic sera of gp and od stimulate erythroid proliferation of their own and each other's erythroid progenitors but not those of h and m. Conversely, m and h recombinant EPOs stimulate not only precursors of their own species but also those of gp and od. Guinea pig or octodon hypoxic serum has no inhibitory effect on human erythroid differentiation. EPO mimicking peptide (EMP-1) stimulates erythroid proliferation of all four species. We cloned the gp EPOR cDNA and obtained a partial gp EPO cDNA clone that is being analyzed. The predicted amino acid sequence of gp EPOR exhibits high homology to those of m and h EPORs. These functional data suggests that the EPO gene of gp and od has diverged from m and h, underscoring their phylogenic distance. The elucidation of this diversity should further our understanding of the functional domains of EPO and EPOR.