Delayed hemoglobin switching and perinatal neocytolysis in mice with gain-of-function erythropoietin receptor

Mutations of the truncated cytoplasmic domain of human erythropoietin receptor (EPOR) result in gain-of-function of erythropoietin (EPO) signaling and a dominantly inherited polycythemia, primary familial and congenital polycythemia (PFCP). We interrogated the unexplained transient absence of perinatal polycythemia observed in PFCP patients using an animal model of PFCP to examine its erythropoiesis during embryonic, perinatal, and early postnatal periods. In this model, we replaced the murine EpoR gene (m EpoR ) with the wild-type human EPOR (wtH EPOR ) or mutant human EPOR gene (mtH EPOR ) and previously reported that the gain-of-function mtH EPOR mice become polycythemic at 3~6 weeks of age, but not at birth, similar to the phenotype of PFCP patients. In contrast, wtH EPOR mice had sustained anemia. We report that the mtH EPOR fetuses are polycythemic, but their polycythemia is abrogated in the perinatal period and reappears again at 3 weeks after birth. mtH EPOR fetuses have a delayed switch from primitive to definitive erythropoiesis, augmented erythropoietin signaling, and prolonged Stat5 phosphorylation while the wtH EPOR fetuses are anemic. Our study demonstrates the in vivo effect of excessive EPO/EPOR signaling on developmental erythropoiesis switch and describes that fetal polycythemia in this PFCP model is followed by transient correction of polycythemia in perinatal life associated with low Epo levels and increased exposure of erythrocytes’ phosphatidylserine. We suggest that neocytolysis contributes to the observed perinatal correction of polycythemia in mtH EPOR newborns as embryos leaving the hypoxic uterus are exposed to normoxia at birth. Key message Human gain-of-function EPOR (mtH EPOR ) causes fetal polycythemia in knock-in mice. Wild-type human EPOR causes fetal anemia in knock-in mouse model. mtH EPOR mice have delayed switch from primitive to definitive erythropoiesis. Polycythemia of mtH EPOR mice is transiently corrected in perinatal life. mtH EPOR newborns have low Epo and increased exposure of erythrocytes’ phosphatidylserine.