title: ER71 acts downstream of BMP, Notch, and Wnt signaling in blood and vessel progenitor specification.
abstract: FLK1-expressing (FLK1(+)) mesoderm generates blood and vessels. Here, we show that combined BMP, Notch, and Wnt signaling is necessary for efficient FLK1(+) mesoderm formation from embryonic stem cells (ESCs). Inhibition of BMP, Notch, and Wnt signaling pathways greatly decreased the generation of FLK1(+) mesoderm and expression of the Ets transcription factor Er71. Enforced expression of ER71 in ESCs resulted in a robust induction of FLK1(+) mesoderm; rescued the generation of FLK1(+) mesoderm when blocked by BMP, Notch, and Wnt inhibition; and enhanced hematopoietic and endothelial cell generation. Er71-deficient mice had greatly reduced FLK1 expression, died early in gestation, and displayed severe blood and vessel defects that are highly reminiscent of the Flk1 null mouse phenotype. Collectively, we provide compelling evidence that ER71 functions downstream of BMP, Notch, and Wnt signals and regulates FLK1(+) mesoderm, blood, and vessel development.
authors.affiliation: National Research Laboratory, Department of Biological Science, KAIST, Daejeon, Korea.
authors.forename: Dongjun
authors.initials: D
authors.lastname: Lee
authors.forename: Changwon
authors.initials: C
authors.lastname: Park
authors.forename: Ho
authors.initials: H
authors.lastname: Lee
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Lugus
authors.forename: Seok Hyung
authors.initials: SH
authors.lastname: Kim
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Arentson
authors.forename: Yun Shin
authors.initials: YS
authors.lastname: Chung
authors.forename: Gustavo
authors.initials: G
authors.lastname: Gomez
authors.forename: Michael
authors.initials: M
authors.lastname: Kyba
authors.forename: Shuo
authors.initials: S
authors.lastname: Lin
authors.forename: Ralf
authors.initials: R
authors.lastname: Janknecht
authors.forename: Dae-Sik
authors.initials: DS
authors.lastname: Lim
authors.forename: Kyunghee
authors.initials: K
authors.lastname: Choi
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000166:cytology; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage; D004151:Dipeptides; D004730:Endothelium, Vascular / Q000166:cytology* / Q000196:embryology / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008648:Mesoderm / Q000166:cytology / Q000196:embryology; D051379:Mice; D018345:Mice, Knockout; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis; D014704:Veratrum Alkaloids / Q000378:metabolism / Q000494:pharmacology; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D004151:Dipeptides; C501127:Dkk1 protein, mouse; C503994:ER71 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D051880:Receptors, Notch; D014157:Transcription Factors; D014704:Veratrum Alkaloids; D051153:Wnt Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2; C000541:cyclopamine