ER71 acts downstream of BMP, Notch, and Wnt signaling in blood and vessel progenitor specification.
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.
Lee
Dongjun
D
National Research Laboratory, Department of Biological Science, KAIST, Daejeon, Korea.
Park
Changwon
C
Lee
Ho
H
Lugus
Jesse J
JJ
Kim
Seok Hyung
SH
Arentson
Elizabeth
E
Chung
Yun Shin
YS
Gomez
Gustavo
G
Kyba
Michael
M
Lin
Shuo
S
Janknecht
Ralf
R
Lim
Dae-Sik
DS
Choi
Kyunghee
K
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
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