1. ETS Factors Regulate Vegf-Dependent Arterial Specification
- Author
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Wythe, Joshua D, Dang, Lan TH, Devine, W Patrick, Boudreau, Emilie, Artap, Stanley T, He, Daniel, Schachterle, William, Stainier, Didier YR, Oettgen, Peter, Black, Brian L, Bruneau, Benoit G, and Fish, Jason E
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Genetics ,1.1 Normal biological development and functioning ,Underpinning research ,Adaptor Proteins ,Signal Transducing ,Animals ,Animals ,Genetically Modified ,Aorta ,Binding Sites ,Calcium-Binding Proteins ,Endocardium ,Enhancer Elements ,Genetic ,Gene Expression Regulation ,Developmental ,Green Fluorescent Proteins ,Human Umbilical Vein Endothelial Cells ,Humans ,Intracellular Signaling Peptides and Proteins ,MAP Kinase Signaling System ,Membrane Proteins ,Mice ,Organ Specificity ,Proto-Oncogene Proteins ,Receptor ,Notch4 ,Receptors ,Notch ,Trans-Activators ,Transcription ,Genetic ,Transcriptional Regulator ERG ,Vascular Endothelial Growth Factor A ,Zebrafish ,Medical and Health Sciences ,Developmental Biology ,Biochemistry and cell biology - Abstract
Vegf signaling specifies arterial fate during early vascular development by inducing the transcription of Delta-like 4 (Dll4), the earliest Notch ligand gene expressed in arterial precursor cells. Dll4 expression precedes that of Notch receptors in arteries, and factors that direct its arterial-specific expression are not known. To identify the transcriptional program that initiates arterial Dll4 expression, we characterized an arterial-specific and Vegf-responsive enhancer of Dll4. Our findings demonstrate that Notch signaling is not required for initiation of Dll4 expression in arteries and suggest that Notch instead functions as a maintenance factor. Importantly, we find that Vegf signaling activates MAP kinase (MAPK)-dependent E26 transformation-specific sequence (ETS) factors in the arterial endothelium to drive expression of Dll4 and Notch4. These findings identify a Vegf/MAPK-dependent transcriptional pathway that specifies arterial identity by activating Notch signaling components and illustrate how signaling cascades can modulate broadly expressed transcription factors to achieve tissue-specific transcriptional outputs.
- Published
- 2013