Erythroid development in the mammalian embryo

Baron, Margaret H.; Vacaru, Andrei M.; Nieves, Johnathan L.

doi:10.1016/j.bcmd.2013.07.006

Cited by 40 publications

(38 citation statements)

References 115 publications

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“…8B). The fetal liver is the principal site of erythropoiesis during mid-to late gestation in mouse embryonic development (49), and the observed increase in heme likely represents a response to lactic acidosis and the impaired oxygen-carrying capacity of fetal hemoglobin. While the late-gestation fetus has adaptive mechanisms to survive acute hypoxia/acidosis during parturition (50), less is known about the fetal response to chronic acidosis.…”

Section: Discussionmentioning

confidence: 99%

Requirement for the Mitochondrial Pyruvate Carrier in Mammalian Development Revealed by a Hypomorphic Allelic Series

Bowman

Zhao

Hartung

et al. 2016

Molecular and Cellular Biology

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bGlucose and oxygen are two of the most important molecules transferred from mother to fetus during eutherian pregnancy, and the metabolic fates of these nutrients converge at the transport and metabolism of pyruvate in mitochondria. Pyruvate enters the mitochondrial matrix through the mitochondrial pyruvate carrier (MPC), a complex in the inner mitochondrial membrane that consists of two essential components, MPC1 and MPC2. Here, we define the requirement for mitochondrial pyruvate metabolism during development with a progressive allelic series of Mpc1 deficiency in mouse. Mpc1 deletion was homozygous lethal in midgestation, but Mpc1 hypomorphs and tissue-specific deletion of Mpc1 presented as early perinatal lethality. The allelic series demonstrated that graded suppression of MPC resulted in dose-dependent metabolic and transcriptional changes. Steady-state metabolomics analysis of brain and liver from Mpc1 hypomorphic embryos identified compensatory changes in amino acid and lipid metabolism. Flux assays in Mpc1-deficient embryonic fibroblasts also reflected these changes, including a dramatic increase in mitochondrial alanine utilization. The mitochondrial alanine transaminase GPT2 was found to be necessary and sufficient for increased alanine flux upon MPC inhibition. These data show that impaired mitochondrial pyruvate transport results in biosynthetic deficiencies that can be mitigated in part by alternative anaplerotic substrates in utero. E mbryonic development in eutherian mammals is defined by ongoing metabolic interactions between mother and fetus. Placentas have evolved a sophisticated suite of adaptations to ensure adequate nutrient, gas, and waste exchange between fetus and mother, as well as hormonal and immunological communication (1, 2). To meet the fetal requirements for nutrient and oxygen consumption during pregnancy, maternal cardiac output increases such that uteroplacental blood flow accounts for ϳ25% of total cardiac output (3). Glucose and oxygen are arguably the two most important molecules transferred from mother to fetus, in terms of both concentration and the multitude of physiological adaptations in place to ensure their adequate transport; however, the requirement for mitochondrial oxidative metabolism during embryonic development remains poorly defined.While oxygen tension in utero is low relative to atmospheric levels, measurement of oxygen consumption and lactate uptake in fetal lambs provided evidence that the fetus is a net consumer rather than a producer of lactate (4). Consistent with this, fetal myocardium consumes a large amount of lactate, in addition to glucose, indicating that oxidative metabolism of carbohydrates is an important energy source in the developing heart (5, 6). Additionally, lactate utilization is high in the neonatal brain, and the capacity for lactate import is higher in the neonatal brain than in the adult brain (7). Together, these observations provide evidence for the importance of mitochondrial oxidative metabolism early in mammalian development. S...

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Section: Discussionmentioning

confidence: 99%

Requirement for the Mitochondrial Pyruvate Carrier in Mammalian Development Revealed by a Hypomorphic Allelic Series

Bowman

Zhao

Hartung

et al. 2016

Molecular and Cellular Biology

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“…Transcriptional regulation of erythroid development has been extensively studied (reviewed in Baron et al, 2013; Dore and Crispino, 2011; Dzierzak and Philipsen, 2013). A core set of transcription factors dictates lineage specificity and maturation of erythroid cells in mammals.…”

Section: Regulation Of Erythroid Developmentmentioning

confidence: 99%

Development and differentiation of the erythroid lineage in mammals

Barminko

Reinholt

Baron

2016

Developmental & Comparative Immunology

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Summary The red blood cell (RBC) is responsible for performing the highly specialized function of oxygen transport, making it essential for survival during gestation and postnatal life. Establishment of sufficient RBC numbers, therefore, has evolved to be a major priority of the postimplantation embryo. The “primitive” erythroid lineage is the first to be specified in the developing embryo proper. Significant resources are dedicated to producing RBCs throughout gestation. Two transient and morphologically distinct waves of hematopoietic progenitor-derived erythropoiesis are observed in development before hematopoietic stem cells (HSCs) take over to produce “definitive” RBCs in the fetal liver. Toward the end of gestation, HSCs migrate to the bone marrow, which becomes the primary site of RBC production in the adult. Erythropoiesis is regulated at various stages of erythroid cell maturation to ensure sufficient production of RBCs in response to physiological demands. Here, we highlight key aspects of mammalian erythroid development and maturation as well as differences among the primitive and definitive erythroid cell lineages.

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“…In mice, progenitors of the primitive erythrocyte lineage arise from the mesoderm during gastrulation in the yolk sac region, called the blood island [1,2]. Subsequently, the definitive hematopoiesis including the production of primitive erythrocytes occurs first in the aortagonad-mesonephros, second in the placenta during embryogenesis, and finally in the fetal liver [3].…”

Section: Introductionmentioning

confidence: 99%

Aminolevulinate synthase 2 mediates erythrocyte differentiation by regulating larval globin expression during Xenopus primary hematopoiesis

Ogawa-Otomo

Kurisaki

Ito

2015

Biochemical and Biophysical Research Communications

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Hemoglobin synthesis by erythrocytes continues throughout a vertebrate's lifetime. The mechanism of mammalian heme synthesis has been studied for many years; aminolevulinate synthase 2 (ALAS2), a heme synthetase, is associated with X-linked dominant protoporphyria in humans. Amphibian and mammalian blood cells differ, but little is known about amphibian embryonic hemoglobin synthesis. We investigated the function of the Xenopus alas2 gene (Xalas2) in primitive amphibian erythrocytes and found that it is first expressed in primitive erythroid cells before hemoglobin alpha 3 subunit (hba3) during primary hematopoiesis and in the posterior ventral blood islands at the tailbud stage. Xalas2 is not expressed during secondary hematopoiesis in the dorsal lateral plate. Hemoglobin was barely detectable by o-dianisidine staining and hba3 transcript levels decreased in Xalas2-knockdown embryos. These results suggest that Xalas2 might be able to synthesize hemoglobin during hematopoiesis and mediate erythrocyte differentiation by regulating hba3 expression in Xenopus laevis.

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Erythroid development in the mammalian embryo

Cited by 40 publications

References 115 publications

Requirement for the Mitochondrial Pyruvate Carrier in Mammalian Development Revealed by a Hypomorphic Allelic Series

Requirement for the Mitochondrial Pyruvate Carrier in Mammalian Development Revealed by a Hypomorphic Allelic Series

Development and differentiation of the erythroid lineage in mammals

Aminolevulinate synthase 2 mediates erythrocyte differentiation by regulating larval globin expression during Xenopus primary hematopoiesis

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