title: Etv2/ER71 induces vascular mesoderm from Flk1+PDGFRα+ primitive mesoderm.
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.
authors.affiliation: Laboratory for Stem Cell Biology, RIKEN Center for Developmental Biology, Kobe, Japan. kataokah@cdb.riken.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kataoka
authors.forename: Misato
authors.initials: M
authors.lastname: Hayashi
authors.forename: Reiko
authors.initials: R
authors.lastname: Nakagawa
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Naoki
authors.initials: N
authors.lastname: Izumi
authors.forename: Satomi
authors.initials: S
authors.lastname: Nishikawa
authors.forename: Martin Lars
authors.initials: ML
authors.lastname: Jakt
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tarui
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Nishikawa
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006413:Hematopoietic System / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D017403:In Situ Hybridization; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000378:metabolism; D008648:Mesoderm / Q000196:embryology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D020411:Oligonucleotide Array Sequence Analysis; D040201:Platelet Membrane Glycoprotein IIb / Q000235:genetics / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics* / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D017493:Leukocyte Common Antigens; D040201:Platelet Membrane Glycoprotein IIb; D020796:Receptor, Platelet-Derived Growth Factor alpha; D014157:Transcription Factors; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099152:Cadherin 5; C503994:ER71 protein, mouse