HIF-1 regulates the expression of multiple genes to stimulate erythropoiesis in response to hypoxia. HIF-1 stimulates production of the EPO in the kidney, which binds to its receptor (EPOR) on erythroid progenitors in the bone marrow (in the adult and yolk sac in the embryo) to stimulate their survival, proliferation, and differentiation. Erythropoiesis involves uptake by the marrow of large amounts of iron, which are used in the synthesis of hemoglobin. In the liver, HIF-1 stimulates iron uptake by repressing the gene encoding hepcidin, which is an inhibitor of ferroportin, the major protein responsible for intestinal iron uptake. HIF-1 also activates hepatic synthesis of transferrin, the major plasma protein responsible for transporting iron from the intestine to the bone marrow via the transferrin receptor. Thus, HIF-1 directly regulates the expression of 5 gene products (EPO, EPOR, hepcidin, transferrin, and transferrin receptor) involving 5 different organs (kidney, liver, intestine, blood, and bone marrow) to control erythropoiesis.