Maturation and enucleation of primitive erythroblasts during mouse embryogenesis is accompanied by changes in cell-surface antigen expression

Fraser, Stuart T.; Isern, Joan; Baron, Margaret H.

doi:10.1182/blood-2006-03-006569

Cited by 151 publications

(257 citation statements)

References 72 publications

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“…Primitive and definitive erythropoiesis can be tracked by measuring CD71 together with Ter119 ( Figure 3a). 8,15 ABC-meÀ/À embryos are severely anemic at day 10.5 pc (Figure 1), when 95% of circulating blood cells are primitive nucleated erythroblasts in WT embryos. 8 Furthermore, a large percentage of these circulating blood cells (70-80% at day 9.5 pc 8 ; around 30-40% at day 10.5; (Figures 3a and b)) harbor high levels of expression and are positive for both CD71 (CD71 þ high ) and Ter119 (Ter119 þ high ).…”

Section: Resultsmentioning

confidence: 99%

“…8,15 ABC-meÀ/À embryos are severely anemic at day 10.5 pc (Figure 1), when 95% of circulating blood cells are primitive nucleated erythroblasts in WT embryos. 8 Furthermore, a large percentage of these circulating blood cells (70-80% at day 9.5 pc 8 ; around 30-40% at day 10.5; (Figures 3a and b)) harbor high levels of expression and are positive for both CD71 (CD71 þ high ) and Ter119 (Ter119 þ high ). Interestingly, in adult definitive erythropoiesis models (i.e., bone marrow), CD71 þ high cells mostly correspond to basophilic and polychromatophilic erythroblasts, in which hemoglobin synthesis rates are maximal 15 (Figure 3a).…”

Section: Resultsmentioning

confidence: 99%

“…8 In Figures 3a and b, we have defined five regions (R1-R5) of a flow cytometry scatter plot according to the expression levels of CD71 and Ter119 in circulating blood cells from day 10.5 embryos. The majority of these cells in day 10.5 WT embryos are CD71 þ high (mostly located in R3, few in R2), consistent with a majority of polychromatophilic and basophilic erythroblasts at this stage in embryonic blood (Figures 3a, b and c and Fraser et al 8 ) Interestingly, the R3 population (the one harboring the highest levels of CD71 expression and therefore high hemoglobin synthesis rates) is almost absent in ABC-meÀ/À embryos (Figures 3b and c). In addition, the R3 population is also reduced (but to a lesser extent) in ABCme þ /À embryos (Figures 3b and c).…”

Section: Resultsmentioning

confidence: 99%

“…6 Furthermore, at day 9.5-10.5 pc, 95% of circulating blood cells are primitive nucleated erythroblasts (most of them basophilic and polychromatophilic) and a large number of these erythroblasts express high levels of transferrin receptor (CD71, responsible for iron uptake and required to synthesize hemoglobin) and Ter119 (membrane protein used as a marker for terminal erythroid differentiation). 8,9 Therefore, maximal iron uptake and hemoglobin synthesis rates in embryonic blood cells occur at the same stage as the detection of ABC-me expression in the yolk sac. In addition, ABC-me (ABCB10) has been demonstrated to be required for maximal (not basal) iron import into mitochondria during in vitro erythroid differentiation, as it stabilizes the iron importer mitoferrin 1 (Mfrn1).…”

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confidence: 99%

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The mitochondrial transporter ABC-me (ABCB10), a downstream target of GATA-1, is essential for erythropoiesis in vivo

et al. 2012

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The mitochondrial transporter ATP binding cassette mitochondrial erythroid (ABC-me/ABCB10) is highly induced during erythroid differentiation by GATA-1 and its overexpression increases hemoglobin production rates in vitro. However, the role of ABC-me in erythropoiesis in vivo is unknown. Here we report for the first time that erythrocyte development in mice requires ABC-me. ABC-meÀ/À mice die at day 12.5 of gestation, showing nearly complete eradication of primitive erythropoiesis and lack of hemoglobinized cells at day 10.5. ABC-meÀ/À erythroid cells fail to differentiate because they exhibit a marked increase in apoptosis, both in vivo and ex vivo. Erythroid precursors are particularly sensitive to oxidative stress and ABC-me in the heart and its yeast ortholog multidrug resistance-like 1 have been shown to protect against oxidative stress. Thus, we hypothesized that increased apoptosis in ABC-meÀ/À erythroid precursors was caused by oxidative stress. Within this context, ABC-me deletion causes an increase in mitochondrial superoxide production and protein carbonylation in erythroid precursors. Furthermore, treatment of ABC-meÀ/À erythroid progenitors with the mitochondrial antioxidant MnTBAP (superoxide dismutase 2 mimetic) supports survival, ex vivo differentiation and increased hemoglobin production. Altogether, our findings demonstrate that ABC-me is essential for erythropoiesis in vivo. Cell Death and Differentiation (2012) 19, 1117-1126 doi:10.1038/cdd.2011; published online 13 January 2012A central event during erythroid development is the induction of the components responsible for heme biosynthesis. Although heme is also produced in non-erythroid cells, its biosynthesis is specifically regulated during erythroid differentiation. 1-3 Thus, mutations in some specific genes involved in heme production have been shown to cause several human blood disorders, such as sideroblastic anemias. 4 This type of anemia is characterized by abnormal erythroid differentiation with a reduction in the total number of erythrocytes. 4 In addition, there are idiopathic anemias (either genetic or druginduced) in which the primary molecular defect is unknown. Recently, a novel bioinformatic approach identified new genes involved in heme biosynthesis that could be potential therapeutic targets for these disorders. 5 Furthermore, this large-scale computational screen identified again the ATP Binding Cassette mitochondrial erythroid transporter (ABCme/ABCB10) as an important protein for heme biosynthesis. 5 We previously identified ABC-me as a downstream target of an essential transcription factor for terminal erythroid differentiation, namely GATA-1. 6 ABC-me is a homodimeric transporter located in the inner mitochondrial membrane, which shows the highest expression levels in erythroid tissues. 6,7 Importantly, during early stages of mouse development (day 10 post coitus, pc), ABC-me expression is detected exclusively at the primitive sites of hematopoiesis, namely the yolk sac blood islands. 6 Furthermore, at day 9.5-10.5 pc,...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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The mitochondrial transporter ABC-me (ABCB10), a downstream target of GATA-1, is essential for erythropoiesis in vivo

et al. 2012

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“…This shift of erythropoiesis from one tissue to another and the change in globin-gene expression are common features of vertebrate erythropoiesis. Mouse and human definitive erythrocytes in the peripheral blood are enucleated, whereas primitive erythrocytes have a nucleus when they are released from yolk sac and complete their maturation (enucleation) while circulating 9,10 .…”

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Erythropoietin production in neuroepithelial and neural crest cells during primitive erythropoiesis

et al. 2013

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Erythropoietin (Epo) supports both primitive erythropoiesis in the yolk sac and definitive erythropoiesis in the fetal liver and bone marrow. Although definitive erythropoiesis requires kidney-and liver-secreted Epo, it is unclear which cells produce Epo for primitive erythropoiesis. Here we find neural Epo-producing (NEP) cells in mid-gestational stage embryos using mouse lines that express green fluorescent protein (GFP) under the Epo gene regulation. In these mice, GFP is expressed exclusively in a subpopulation of neural and neural crest cells at embryonic day 9.0 when Epo-deficient embryos exhibit abnormalities in primitive erythropoiesis. The GFP-positive NEP cells express Epo mRNA and the ex vivo culture of embryonic day 8.5 neural tubes results in the secretion of Epo, which is able to induce the proliferation and differentiation of yolk sac-derived erythroid cells. These results thus suggest that NEP cells secrete Epo and might support the development of primitive erythropoiesis.

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Hematopoietic stem cell‐independent hematopoiesis: emergence of erythroid, megakaryocyte, and myeloid potential in the mammalian embryo

2016

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Steady‐state production of all circulating blood cells in the adult ultimately depends on hematopoietic stem cells (HSCs), which first arise in small numbers beginning at embryonic day (E) 10.5 in large arterial vessels of the murine embryo. However, blood cell synthesis first begins in the yolk sac beginning at E7.25 and consists of two waves of hematopoietic progenitors. The first wave consists of primitive erythroid, megakaryocyte, and macrophage progenitors that rapidly give rise to maturing blood cells of all three lineages. This ‘primitive’ wave of progenitors is followed by a partially overlapping wave of ‘erythro‐myeloid progenitors’, which contain definitive erythroid, megakaryocyte, macrophage, neutrophil, and mast cell progenitors that seed the fetal liver and jump‐start hematopoiesis before the engraftment and expansion of HSCs. These two waves of progenitors that arise in the yolk sac are necessary and even sufficient to sustain the survival of the mouse embryo until birth in the absence of HSCs. They provide key signals to support HSC emergence. Finally, HSC‐independent hematopoiesis also provides long‐lived tissue‐resident macrophage populations that function in multiple adult organs.

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Maturation and enucleation of primitive erythroblasts during mouse embryogenesis is accompanied by changes in cell-surface antigen expression

Cited by 151 publications

References 72 publications

The mitochondrial transporter ABC-me (ABCB10), a downstream target of GATA-1, is essential for erythropoiesis in vivo

The mitochondrial transporter ABC-me (ABCB10), a downstream target of GATA-1, is essential for erythropoiesis in vivo

Erythropoietin production in neuroepithelial and neural crest cells during primitive erythropoiesis

Hematopoietic stem cell‐independent hematopoiesis: emergence of erythroid, megakaryocyte, and myeloid potential in the mammalian embryo

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