Hematopoiesis in mammalian embryos proceeds through three successive waves of hematopoietic progenitors. Since their emergence spatially and temporally overlap and phenotypic markers are often shared, the specifics regarding their origin, development, lineage restriction and mutual relationships have not been fully determined. The identification of wave-specific markers would aid to resolve these uncertainties. Here, we show that toll-like receptors (TLRs) are expressed during early mouse embryogenesis. We provide phenotypic and functional evidence that the expression of TLR2 on E7.5 c-kit+ cells marks the emergence of precursors of erythro-myeloid progenitors (EMPs) and provides resolution for separate tracking of EMPs from primitive progenitors. Using in vivo fate mapping, we show that at E8.5 the Tlr2 locus is already active in emerging EMPs and in progenitors of adult hematopoietic stem cells (HSC). Together, this data demonstrates that the activation of the Tlr2 locus tracks the earliest events in the process of EMP and HSC specification.

• MeSH
• dospělé kmenové buňky metabolismus   MeSH
• hematopoetické kmenové buňky metabolismus   MeSH
• hematopoéza MeSH
• myši inbrední C57BL MeSH
• myši embryologie   genetika   metabolismus   MeSH
• protoonkogenní proteiny c-kit genetika   metabolismus   MeSH
• toll-like receptor 2 genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši embryologie   genetika   metabolismus   MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• protoonkogenní proteiny c-kit MeSH
• toll-like receptor 2 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.

• Klíčová slova
• Augmented Stat5 signaling, Fetal polycythemia, Human EPOR mutation, Neocytolysis, Prolonged primitive erythropoiesis,
• 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
• Názvy látek
• erythropoetin MeSH
• hemoglobiny MeSH
• receptory erythropoetinu MeSH
• transkripční faktor STAT5 MeSH