Single-lineage transcriptome analysis reveals key regulatory pathways in primitive erythroid progenitors in the mouse embryo

Isern, Joan; He, Zhiyong; Fraser, Stuart T.; Nowotschin, Sonja; Ferrer-Vaquer, Anna; Moore, Rebecca; Hadjantonakis, Anna-Katerina; Schulz, Vincent P.; Tuck, David; Gallagher, Patrick G.; Baron, Margaret H.

doi:10.1182/blood-2010-10-313676

Cited by 65 publications

(176 citation statements)

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“…7,12 Primitive erythropoiesis may involve a limited hierarchy of progenitors in which a bipotential megakaryocyte-erythroid progenitor gives rise to unipotential EryP progenitors. In the mouse embryo, the first megakaryocytes, identified by staining for surface GP1b␤, are found in the yolk sac at E9.5 and in the blood at E10.5, substantially later than primitive erythroblasts.…”

Section: Primitive Erythroid Progenitorsmentioning

confidence: 99%

“…Primitive erythropoiesis is transient: EryP progenitors are produced in the yolk sac of the embryo for only a brief period (ϳ 2 days). 7,12 Their terminally differentiated progeny persist in the circulation through the end of gestation and even for a while after birth. 13 However, they are rapidly outnumbered by the rapidly expanding population of definitive erythroid cells (EryD) arising from the growing fetal liver.…”

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confidence: 99%

“…12 That the Wnt pathway is active and functions autonomously in EryP progenitors was suggested by immunostaining for activated (stabilized) ␤-catenin and by fluorescence of a nuclear-GFP Wnt/␤-catenin reporter in the blood islands of the yolk sac. 12 Submitted January 1, 2012; accepted February 9, 2012. Prepublished online as Blood First Edition paper, February 15, 2012; DOI 10.1182 DOI 10.…”

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confidence: 99%

“…12 EryP progenitors express another receptor tyrosine kinase receptor, Tie-2, 12,45 but their growth was not consistently stimulated by addition of a recombinant Tie2 ligand, angiopoietin-1. 12 It is possible that functions for c-kit and/or Tie-2 signaling could be unmasked by development of serum-free culture conditions for EryP progenitors. 12 The TGF-␤ pathway has been implicated in embryonic erythroid development.…”

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confidence: 99%

“…TGF-␤1 (but not TGF-␤2 or TGF-␤3) showed a dose-dependent effect on EryP progenitor activity in vitro: growth of EryP progenitors was inhibited at a low concentration and stimulated at higher concentrations of this cytokine. 12 The TGF-␤ signaling pathway may function via an autocrine or paracrine mechanism, as both the receptor and its ligand, Tgf␤1, are transcribed in EryP. 12 In contrast, TGF-␤1 has been viewed as an inhibitor of definitive erythropoiesis in vitro, decreasing proliferation of progenitors and inducing their differentiation.…”

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The embryonic origins of erythropoiesis in mammals

Baron

Isern

Fraser

2012

Blood

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Erythroid (red blood) cells are the first cell type to be specified in the postimplantation mammalian embryo and serve highly specialized, essential functions throughout gestation and postnatal life. The existence of 2 developmentally and morphologically distinct erythroid lineages, primitive (embryonic) and definitive (adult), was described for the mammalian embryo more than a century ago. Cells of the primitive erythroid lineage support the transition from rapidly growing embryo to fetus, whereas definitive erythrocytes function during the transition from fetal life to birth and continue to be crucial for a variety of normal physiologic processes. Over the past few years, it has become apparent that the ontogeny and maturation of these lineages are more complex than previously appreciated. In this review, we highlight some common and distinguishing features of the red blood cell lineages and summarize advances in our understanding of how these cells develop and differentiate throughout mammalian ontogeny. (Blood. 2012;119(21):4828-4837) IntroductionDuring embryonic development, hematopoiesis functions in the rapid production of large numbers of erythroid cells that support the growth and survival of the embryo/fetus and, later, in the generation of a pool of hematopoietic stem cells (HSCs) that persist throughout the life of the adult animal. 1,2 Hematopoiesis in the developing vertebrate embryo occurs in multiple waves and in several different anatomic sites ( Figure 1). The first wave occurs in the yolk sac in both mouse and humans [3][4][5] and produces primarily primitive erythroid cells (EryP) as well as macrophages and megakaryocytes. 3,6 The second wave also arises in the yolk sac but is "definitive," composing erythroid, megakaryocyte, and several myeloid lineages. 7,8 The third wave emerges from HSCs produced within the major arteries of the embryo, yolk sac, and placenta. [1][2][3]9 HSCs home to and expand within the fetal liver and eventually seed the bone marrow. 10,11 Definitive erythroid cells are produced continuously from HSCs in the bone marrow throughout postnatal life. 1,2 Before the initiation of definitive (adult-type) hematopoiesis from multipotent stem cells in the fetal liver, the embryonic circulation is dominated by large, nucleated erythroid cells of the EryP lineage. Primitive erythropoiesis is transient: EryP progenitors are produced in the yolk sac of the embryo for only a brief period (ϳ 2 days). 7,12 Their terminally differentiated progeny persist in the circulation through the end of gestation and even for a while after birth. 13 However, they are rapidly outnumbered by the rapidly expanding population of definitive erythroid cells (EryD) arising from the growing fetal liver. 13,14 Failure in primitive erythropoiesis (as observed, for example, after targeted disruption of genes encoding the transcription factors Gata-1, Gata-2, Lmo2, or Scl) is uniformly associated with embryonic lethality. 1,15 The importance of this lineage is underscored by the fact that primitive erythro...

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Section: Primitive Erythroid Progenitorsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The embryonic origins of erythropoiesis in mammals

Baron

Isern

Fraser

2012

Blood

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155

153

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Analysis of primitive erythroid cell proliferation and enucleation using a cyan fluorescent reporter in transgenic mice

Vacaru

Isern

Fraser

et al. 2013

Genesis

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Primitive erythropoiesis is a vital process for mammalian embryonic development. Here we report the generation and characterization of a new transgenic mouse line that expresses a histone H2B-CFP fusion protein in the nuclei of primitive erythroid cells. We demonstrate the potential of this ε-globin-histone H2B-CFP line for multicolor imaging and flow cytometry analysis. The ε-globin-H2B-CFP line was used to analyze the cell cycle distribution and proliferation of CFP-expressing primitive erythroblasts from E8.5–E13.5. We also evaluated phagocytosis of extruded CFP-positive nuclei by macrophages in fetal liver and placenta. The ε-globin-H2B-CFP transgenic mouse line adds to the available tools for studying the development of the primitive erythroid lineage.

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Neuropilin‐2 genomic elements drive cre recombinase expression in primitive blood, vascular and neuronal lineages

Wiszniak

Scherer

Ramshaw

et al. 2015

Genesis

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We have established a novel Cre mouse line, using genomic elements encompassing the Nrp2 locus, present within a bacterial artificial chromosome clone. By crossing this Cre driver line to R26R LacZ reporter mice, we have documented the temporal expression and lineage traced tissues in which Cre is expressed. Nrp2-Cre drives expression in primitive blood cells arising from the yolk sac, venous and lymphatic endothelial cells, peripheral sensory ganglia, and the lung bud. This mouse line will provide a new tool to researchers wishing to study the development of various tissues and organs in which this Cre driver is expressed, as well as allow tissue-specific knockout of genes of interest to study protein function. This work also presents the first evidence for expression of Nrp2 protein in a mesodermal progenitor with restricted hematopoietic potential, which will significantly advance the study of primitive erythropoiesis. genesis 53:709-717, 2015. © 2015 Wiley Periodicals, Inc.

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Single-lineage transcriptome analysis reveals key regulatory pathways in primitive erythroid progenitors in the mouse embryo

Cited by 65 publications

References 44 publications

The embryonic origins of erythropoiesis in mammals

The embryonic origins of erythropoiesis in mammals

Analysis of primitive erythroid cell proliferation and enucleation using a cyan fluorescent reporter in transgenic mice

Neuropilin‐2 genomic elements drive cre recombinase expression in primitive blood, vascular and neuronal lineages

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