Erythropoietin receptors that signal through Stat5 or Stat3 support fetal liver and adult erythropoiesis: Lack of specificity of stat signals during red blood cell development

Erythropoietin (Epo) is essential for formation of mature red blood cells ( RBC). However, the function of Epo receptor (EpoR)-dependent signaling path ways in the regulation of erythropoiesis remains unclear. To determine whet her specific Stat signals are required for RBC development, we changed the Stat signaling specificity of the EpoR. The wild-type EpoR activates only S tat5. Thus, we substituted the major Stat5 binding sites (residues 343 and 401) in the EpoR cytoplasmic region with the Stat3 binding/activation motif from gp130. We demonstrated that activated EpoRs containing a single subst itution stimulate Stat5 and Stat3, whereas an EpoR with both substitutions stimulates Stat3 but not Stat5. We then determined the ability of these rec eptors to support fetal liver and adult erythropoiesis. Our results show th at erythropoiesis is stimulated by EpoRs that activate Stat5, both Stat5 an d Stat3, or Stat3 in place of Stat5. These findings demonstrate that the sp ecificity of EpoR Stat signaling is not essential for RBC development.