ETV2 expression marks blood and endothelium precursors, including hemogenic endothelium, at the onset of blood development

Abstract

Background: ETV2 has been identified as an important player in embryonic hematopoiesis. However, the cell populations in which this transcription factor is expressed and operates during blood specification remain to be fully characterized. Here we address these issues using ES cells and a transgenic mouse line expressing green fluorescent protein (GFP) under the control of ETV2 regulatory elements, allowing us to observe the tight association between ETV2 expression and the initiation of hematopoiesis. Results: Both in differentiating ES cells and gastrulating embryos ETV2::GFP is mostly found co‐expressed with endothelial markers and defines a subset of cells with greatly enriched primitive erythroid potential. Upon culture ETV2::GFP cells rapidly up‐regulate CD41, down‐regulate endothelium cell surface markers and generate definitive hematopoietic progenitors. Altogether these characteristics represent the hallmark of hemogenic endothelium cells, a specialized endothelium originating from the hemangioblast and giving rise to hematopoietic cells. Importantly, ETV2 deficiency results in a complete absence of hemogenic endothelium in differentiating ES cells and gastrulating embryos. Conclusions: Altogether our data reveal that ETV2 marks hemogenic endothelium in gastrulating embryos and is absolutely required for the formation of this precursor at the onset of hematopoiesis. These results enhance our understanding of embryonic hematopoiesis and the factors driving hemogenic endothelium specification. Developmental Dynamics 241:1454–1464, 2012. © 2012 Wiley Periodicals, Inc.

FOXF1 inhibits hematopoietic lineage commitment during early mesoderm specification

“…Finally, global transcriptomic analysis revealed the expression of many transcriptional regulators of hematopoietic and/ or endothelial fate including Etv2 in the FLK1 + FOXF1::VENUS + population. Given that the allantois is the main mesodermal tissue where both FOXF1 and ETV2 are expressed at the E7.5 stage of development (Kataoka et al, 2011;Wareing et al, 2012a), these FLK1 + FOXF1::VENUS + ETV2 + cells are most likely localized to this mesoderm derivative which has been shown previously to give rise to hematopoiesis autonomously (Zeigler et al, 2006). Altogether, these findings reveal that in gastrulating embryos a subset of FOXF1-expressing cells can give rise to hematopoietic cells.…”

“…We and others have previously shown that the ETS transcription factor ETV2 is expressed in mesodermal progenitors which give rise to both hematopoietic and vascular system, and that Etv2 −/− embryos lack both lineages (Kataoka et al, 2011;Lee et al, 2008;Wareing et al, 2012b). Whilst FLK1 + cells are still detected at the expected frequency in Etv2 −/− embryos, the TIE2 + population is drastically reduced (Wareing et al, 2012a); we therefore analyzed the co-expression of FOXF1::VENUS and TIE2 in wild-type, heterozygous or homozygous null Etv2 embryos (Fig. 4D).…”

LSD1/KDM1A promotes hematopoietic commitment of hemangioblasts through downregulation of Etv2

“…It is interesting that the expression of mouse Etv2 was transiently detected in the beginning of hematopoiesis and was barely detectable in hematopoietic tissues at later stages, such as the aortagonad-mesonephros and fetal liver in embryos and in the bone marrow and spleen in adults (54)(55)(56). A dramatic down-regulation of Etv2 during hematopoietic differentiation is also observed in zebrafish (35) and Xenopus (57).…”

The Role of Runx1 in Embryonic Blood Cell Formation

“…Etv2 + Flk1 + mesodermal cells give rise to both endothelial cells and blood (Kataoka et al, 2011, Wareing et al, 2012). Whether the Etv2 + Flk1 + mesodermal progenitor gives rise to a non-hemogenic endothelial cell or a HE cell was recently reported to be controlled, at least in part, by Runx1 (Eliades et al, 2016).…”