Characterization Of Iron Metabolism In Mouse Model Of Congenital Polycythemia With Human Gain-Of-Function Erythropoietin Receptor

Hepcidin (encoded by HAMP), the peptide hormone regulating systemic iron homeostasis, controls iron flux to plasma and thus ensures adequate iron supply for erythropoiesis. Increased erythropoietic activity negatively regulates hepcidin synthesis by the hormone erythroferrone (ERFE) produced by erythroid precursors in response to erythropoietin (EPO). Here we evaluated iron metabolism in a mouse model of polycythemia with augmented erythropoiesis and low EPO levels bearing the gain-of-function polycythemia-causing human EPO receptor gene (mtHEPOR) (Divoky PNAS 2002). The mtHEPOR embryos developed polycythemia around embryonic day (ED) 17.5, followed by unexpected but transient correction of polycythemia in perinatal life (postnatal day 7 - PD7) and reappearance of a polycythemic phenotype at 3-6 weeks of age. (Human patients with the gain-of-function polycythemia-causing human EPOR mutations are also born non-polycythemic and then develop polycythemia within a few weeks of neonatal life). The mtHEPOR mice had reduced Epo levels, augmented EPOR signaling and prolonged activation of Stat5 in erythroblasts when compared to mEpoR mice (Divoky JMolMed 2016). To assess whether developmental changes of erythron in this mouse model correlate with changes in iron metabolism, we determined temporal changes of Erfe and Hamp expression and body iron stores.