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Delayed hemoglobin switching and perinatal neocytolysis in mice with
gain-of-function erythropoietin receptor
#MMPMID26706855
Divoky V
; Song J
; Horvathova M
; Kralova B
; Votavova H
; Prchal JT
; Yoon D
J Mol Med (Berl)
2016[May]; 94
(5
): 597-608
PMID26706855
show ga
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 (mEpoR) with the wild-type human
EPOR (wtHEPOR) or mutant human EPOR gene (mtHEPOR) and previously reported that
the gain-of-function mtHEPOR mice become polycythemic at 3~6 weeks of age, but
not at birth, similar to the phenotype of PFCP patients. In contrast, wtHEPOR
mice had sustained anemia. We report that the mtHEPOR fetuses are polycythemic,
but their polycythemia is abrogated in the perinatal period and reappears again
at 3 weeks after birth. mtHEPOR fetuses have a delayed switch from primitive to
definitive erythropoiesis, augmented erythropoietin signaling, and prolonged
Stat5 phosphorylation while the wtHEPOR 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 mtHEPOR newborns as embryos leaving the hypoxic uterus are
exposed to normoxia at birth. KEY MESSAGE: Human gain-of-function EPOR (mtHEPOR)
causes fetal polycythemia in knock-in mice. Wild-type human EPOR causes fetal
anemia in knock-in mouse model. mtHEPOR mice have delayed switch from primitive
to definitive erythropoiesis. Polycythemia of mtHEPOR mice is transiently
corrected in perinatal life. mtHEPOR newborns have low Epo and increased exposure
of erythrocytes' phosphatidylserine.
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