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 F...

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Bibliographic Details
Published in:Cell stem cell 2008-05, Vol.2 (5), p.497-507
Main Authors: Lee, Dongjun, Park, Changwon, Lee, Ho, Lugus, Jesse J, Kim, Seok Hyung, Arentson, Elizabeth, Chung, Yun Shin, Gomez, Gustavo, Kyba, Michael, Lin, Shuo, Janknecht, Ralf, Lim, Dae-Sik, Choi, Kyunghee
Format: Article
Language:English
Subjects:
Animals
Blood Vessels - cytology
Bone Morphogenetic Protein 4 - metabolism
Cell Differentiation - physiology
Cell Lineage
Dipeptides
Endothelium, Vascular - cytology
Endothelium, Vascular - embryology
Endothelium, Vascular - physiology
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - physiology
Intercellular Signaling Peptides and Proteins - metabolism
Male
Mesoderm - cytology
Mesoderm - embryology
Mice
Mice, Knockout
Receptors, Notch - metabolism
Signal Transduction
Stem Cells - cytology
Stem Cells - physiology
Transcription Factors - physiology
Vascular Endothelial Growth Factor Receptor-2 - biosynthesis
Veratrum Alkaloids - metabolism
Veratrum Alkaloids - pharmacology
Wnt Proteins - metabolism
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Summary: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.
ISSN:1934-5909
1875-9777
1875-9777
DOI:10.1016/j.stem.2008.03.008