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Blood. 2011 Dec 22;118(26):6975-86. doi: 10.1182/blood-2011-05-352658. Epub 2011 Sep 12.

Etv2/ER71 induces vascular mesoderm from Flk1+PDGFRα+ primitive mesoderm.

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1
Laboratory for Stem Cell Biology, RIKEN Center for Developmental Biology, Kobe, Japan. kataokah@cdb.riken.jp

Abstract

Etv2 (Ets Variant 2) has been shown to be an indispensable gene for the development of hematopoietic cells (HPCs)/endothelial cells (ECs). However, how Etv2 specifies the mesoderm-generating HPCs/ECs remains incompletely understood. In embryonic stem cell (ESC) differentiation culture and Etv2-null embryos, we show that Etv2 is dispensable for generating primitive Flk-1(+)/PDGFRα(+) mesoderm but is required for the progression of Flk-1(+)/PDGFRα(+) cells into vascular/hematopoietic mesoderm. Etv2-null ESCs and embryonic cells were arrested as Flk-1(+)/PDGFRα(+) and failed to generate Flk-1(+)/PDGFRα(-) mesoderm. Flk-1(+)/Etv2(+) early embryonic cells showed significantly higher hemato-endothelial potential than the Flk-1(+)/Etv2(-) population, suggesting that Etv2 specifies a hemato-endothelial subset of Flk-1(+) mesoderm. Critical hemato-endothelial genes were severely down-regulated in Etv2-null Flk-1(+) cells. Among those genes Scl, Fli1, and GATA2 were expressed simultaneously with Etv2 in early embryos and seemed to be critical targets. Etv2 reexpression in Etv2-null cells restored the development of CD41(+), CD45(+), and VE-cadherin(+) cells. Expression of Scl or Fli1 alone could also restore HPCs/ECs in the Etv2-null background, indicating that these 2 genes are critical downstream targets. Furthermore, VEGF induced Etv2 potently and rapidly in Flk-1(+) mesoderm. We propose that Flk-1(+)/PDGFRα(+) primitive mesoderm is committed into Flk-1(+)/PDGFRα(-) vascular mesoderm through Etv2 and that up-regulation of Etv2 by VEGF promotes this commitment.

PMID:
21911838
DOI:
10.1182/blood-2011-05-352658
[Indexed for MEDLINE]
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