Iron availability for erythropoiesis is controlled by the iron-regulatory hormone hepcidin. 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-of-function mutation of human EPO receptor (mtHEPOR) with low EPO characterized by postnatal erythrocytosis. We previously created a mouse model of this mtHEPOR that develops fetal erythrocytosis with a transient perinatal amelioration of erythrocytosis and its reappearance at 3-6 weeks of age. Prenatally and perinatally, mtHEPOR heterozygous and homozygous mice (differing in erythrocytosis severity) had increased Erfe 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 mtHEPOR heterozygotes and homozygotes, accompanied by low Erfe induction and iron accumulation. With aging, the old, especially mtHEPOR homozygotes had a decline of erythropoiesis, myeloid expansion, and local bone marrow inflammatory stress. In addition, mtHEPOR erythrocytes had a reduced lifespan. This, together with reduced iron demand for erythropoiesis, due to its age-related attenuation, likely contributes to increased iron deposition in the aged mtHEPOR mice. In conclusion, the erythroid drive-mediated inhibition of hepcidin production in mtHEPOR mice in the prenatal/perinatal period is postnatally abrogated by increasing iron stores promoting hepcidin synthesis. The differences observed in studied characteristics between mtHEPOR heterozygotes and homozygotes suggest dose-dependent alterations of downstream EPOR stimulation.

• MeSH
• aktivační mutace MeSH
• dospělí MeSH
• erythropoetin * genetika   farmakologie   MeSH
• erytropoéza genetika   MeSH
• hepcidiny genetika   metabolismus   MeSH
• hormony MeSH
• lidé MeSH
• myši MeSH
• polycytemie * genetika   MeSH
• receptory erythropoetinu genetika   metabolismus   MeSH
• senioři MeSH
• železo metabolismus   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• myši MeSH
• senioři MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• autoimunitní hemolytická anemie farmakoterapie   genetika   MeSH
• beta-globiny genetika   izolace a purifikace   MeSH
• bronchiální astma genetika   MeSH
• buněčná diferenciace MeSH
• chelátory železa terapeutické užití   MeSH
• dítě MeSH
• erythropoetin metabolismus   MeSH
• erytrocyty fyziologie   MeSH
• erytropoéza genetika   MeSH
• kultivované buňky MeSH
• lidé MeSH
• proliferace buněk MeSH
• receptory erythropoetinu metabolismus   MeSH
• regulace genové exprese MeSH
• sekvenování exomu MeSH
• signální transdukce MeSH
• stupeň závažnosti nemoci MeSH
• transkripční faktor STAT3 genetika   MeSH
• transkripční faktor STAT5 metabolismus   MeSH
• zárodečné mutace genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH

UNLABELLED: 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.

• MeSH
• aktivační mutace * MeSH
• anemie krev   genetika   metabolismus   MeSH
• erythropoetin metabolismus   MeSH
• erytrocyty metabolismus   MeSH
• erytroidní prekurzorové buňky metabolismus   MeSH
• erytropoéza genetika   MeSH
• fosforylace MeSH
• genotyp MeSH
• hematokrit MeSH
• hemoglobiny genetika   MeSH
• lidé MeSH
• myši transgenní MeSH
• myši MeSH
• polycytemie krev   genetika   metabolismus   MeSH
• receptory erythropoetinu genetika   metabolismus   MeSH
• regulace genové exprese * MeSH
• signální transdukce MeSH
• transkripční faktor STAT5 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

The role of somatic JAK2 mutations in clonal myeloproliferative neoplasms (MPNs) is well established. Recently, germ line JAK2 mutations were associated with polyclonal hereditary thrombocytosis and triple-negative MPNs. We studied a patient who inherited 2 heterozygous JAK2 mutations, E846D from the mother and R1063H from the father, and exhibited erythrocytosis and megakaryocytic atypia but normal platelet number. Culture of erythroid progenitors from the patient and his parents revealed hypersensitivity to erythropoietin (EPO). Using cellular models, we show that both E846D and R1063H variants lead to constitutive signaling (albeit much weaker than JAK2 V617F), and both weakly hyperactivate JAK2/STAT5 signaling only in the specific context of the EPO receptor (EPOR). JAK2 E846D exhibited slightly stronger effects than JAK2 R1063H and caused prolonged EPO-induced phosphorylation of JAK2/STAT5 via EPOR. We propose that JAK2 E846D predominantly contributes to erythrocytosis, but is not sufficient for the full pathological phenotype to develop. JAK2 R1063H, with very weak effect on JAK2/STAT5 signaling, is necessary to augment JAK2 activity caused by E846D above a threshold level leading to erythrocytosis with megakaryocyte abnormalities. Both mutations were detected in the germ line of rare polycythemia vera, as well as certain leukemia patients, suggesting that they might predispose to hematological malignancy.

• MeSH
• dospělí MeSH
• fosforylace MeSH
• Janus kinasa 2 genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• megakaryocyty metabolismus   patologie   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• polycytemie vrozené   genetika   MeSH
• receptory erythropoetinu genetika   metabolismus   MeSH
• signální transdukce MeSH
• transkripční faktor STAT5 genetika   metabolismus   MeSH
• zárodečné mutace genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

• MeSH
• anemie * etiologie   farmakoterapie   MeSH
• chronické selhání ledvin * komplikace   patofyziologie   MeSH
• citráty farmakologie   terapeutické užití   MeSH
• dialýza ledvin škodlivé účinky   MeSH
• erytropoéza účinky léků   MeSH
• hemodialyzační roztoky chemie   terapeutické užití   MeSH
• lidé MeSH
• receptory erythropoetinu metabolismus   MeSH
• rekombinantní proteiny farmakologie   metabolismus   MeSH
• železité sloučeniny terapeutické užití   MeSH
• Check Tag
• lidé MeSH

Erythropoietin (EPO), known for its role in erythroid differentiation, has been suggested to have a direct protective role against a variety of neurotoxic insults. In the present study, we investigated the expression of EPO receptor (EPOR) and the number of EPORpositive cells in three encephalic regions (ventral mesencephalon, striatum, cortex) following lesion induced by 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP). C57BL/6 mice underwent intraperitoneal injection of MPTP at 24 h intervals for 5 days, and their brains were examined 1, 2, 4, 7, 14 or 21 days after the last injection. Western blot and immunohistochemistry analysis revealed that EPOR was dramatically up-regulated in the ventral mesencephalon, 4 days after MPTP insult until the day 21. In contrast, there was a baseline level of EPOR in the striatum and cortex. At subsequent time points after MPTP injury, the levels of EPOR in the two regions were not statistically different compared with those in normal animals. These results suggest that the regional specific up-regulation of EPOR at an early stage after MPTP stimulus may represent a pro-survival mechanism against neurotoxin injury in Parkinsonian model.

• MeSH
• corpus striatum metabolismus   MeSH
• financování organizované MeSH
• imunohistochemie MeSH
• modely nemocí na zvířatech MeSH
• mozková kůra metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• parkinsonské poruchy metabolismus   MeSH
• receptory erythropoetinu metabolismus   MeSH
• substantia nigra metabolismus   MeSH
• upregulace fyziologie   MeSH
• western blotting MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH

• MeSH
• chemokin CXCL12 genetika   metabolismus   MeSH
• erythropoetin metabolismus   MeSH
• financování organizované MeSH
• hypoxie buňky MeSH
• krysa rodu rattus MeSH
• látky indukující angiogenezi metabolismus   MeSH
• messenger RNA metabolismus   MeSH
• novorozená zvířata MeSH
• orgánové kultury - kultivační techniky MeSH
• počet buněk MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• potkani Wistar MeSH
• receptory CXCR4 genetika   metabolismus   MeSH
• receptory erythropoetinu genetika   metabolismus   MeSH
• sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
• techniky in vitro MeSH
• vaskulární endoteliální růstový faktor A genetika   metabolismus   MeSH
• viabilita buněk MeSH
• vláskové buňky MeSH
• vnitřní ucho cytologie   metabolismus   zranění   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH