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Increased erythropoiesis negatively regulates hepcidin synthesis by erythroferrone (ERFE), a hormone produced by erythroid precursors in response to erythropoietin (EPO). The mechanisms coordinating erythropoietic activity with iron homeostasis in erythrocytosis with low EPO are not well defined as exemplified by dominantly inherited (heterozygous) gain\u2010of\u2010function mutation of human EPO receptor (<jats:italic>mtHEPOR<\/jats:italic>) with low EPO characterized by postnatal erythrocytosis. We previously created a mouse model of this <jats:italic>mtHEPOR<\/jats:italic> that develops fetal erythrocytosis with a transient perinatal amelioration of erythrocytosis and its reappearance at 3\u20136\u2009weeks of age. Prenatally and perinatally, <jats:italic>mtHEPOR<\/jats:italic> heterozygous and homozygous mice (differing in erythrocytosis severity) had increased <jats:italic>Erfe<\/jats:italic> transcripts, reduced hepcidin, and iron deficiency. Epo was transiently normal in the prenatal life; then decreased at postnatal day 7, and remained reduced in adulthood. Postnatally, hepcidin increased in <jats:italic>mtHEPOR<\/jats:italic> heterozygotes and homozygotes, accompanied by low Erfe induction and iron accumulation. With aging, the old, especially <jats:italic>mtHEPOR<\/jats:italic> homozygotes had a decline of erythropoiesis, myeloid expansion, and local bone marrow inflammatory stress. In addition, <jats:italic>mtHEPOR<\/jats:italic> erythrocytes had a reduced lifespan. This, together with reduced iron demand for erythropoiesis, due to its age\u2010related attenuation, likely contributes to increased iron deposition in the aged <jats:italic>mtHEPOR<\/jats:italic> mice. In conclusion, the erythroid drive\u2010mediated inhibition of hepcidin production in <jats:italic>mtHEPOR<\/jats:italic> mice in the prenatal\/perinatal period is postnatally abrogated by increasing iron stores promoting hepcidin synthesis. The differences observed in studied characteristics between <jats:italic>mtHEPOR<\/jats:italic> heterozygotes and homozygotes suggest dose\u2010dependent alterations of downstream EPOR stimulation.<\/jats:p>","DOI":"10.1002\/ajh.26658","type":"journal-article","created":{"date-parts":[[2022,7,11]],"date-time":"2022-07-11T11:10:01Z","timestamp":1657537801000},"page":"1286-1299","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Developmental changes in iron metabolism and erythropoiesis in mice with human gain\u2010of\u2010function erythropoietin receptor"],"prefix":"10.1002","volume":"97","author":[{"given":"Barbora","family":"Kralova","sequence":"first","affiliation":[{"name":"Department of Biology, Faculty of Medicine and Dentistry Palacky University  Olomouc Czech 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