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

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...

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Veröffentlicht in:Blood 2011-12, Vol.118 (26), p.6975-6986
Hauptverfasser: Kataoka, Hiroshi, Hayashi, Misato, Nakagawa, Reiko, Tanaka, Yosuke, Izumi, Naoki, Nishikawa, Satomi, Jakt, Martin Lars, Tarui, Hiroshi, Nishikawa, Shin-Ichi
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Sprache:eng
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Zusammenfassung: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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2011-05-352658