ETS Factors Regulate Vegf-Dependent Arterial Specification

• Published in: Developmental cell 2013-07, Vol.26 (1), p.45-58
• Main Authors: Wythe, Joshua D., Dang, Lan T.H., Devine, W. Patrick, Boudreau, Emilie, Artap, Stanley T., He, Daniel, Schachterle, William, Stainier, Didier Y.R., Oettgen, Peter, Black, Brian L., Bruneau, Benoit G., Fish, Jason E.
• Format: Article
• Language: English
• Subjects: Animals; Animals, Genetically Modified - embryology; Animals, Genetically Modified - metabolism; Aorta - metabolism; Aorta - physiology; Binding Sites; Endocardium - embryology; Endocardium - metabolism; Enhancer Elements, Genetic; Gene Expression Regulation, Developmental; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; MAP Kinase Signaling System; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Organ Specificity; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Receptor, Notch4; Receptors, Notch - genetics; Receptors, Notch - metabolism; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription, Genetic; Transcriptional Regulator ERG; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Zebrafish - embryology; Zebrafish - genetics; Zebrafish - metabolism
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2013.06.007

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. [Display omitted] •Identification of a Vegf/MAPK-dependent arterial-specific enhancer of Dll4•Enhancer activity requires ETS transcription factors•Vegf/MAPK signaling drives recruitment of ETS factors to Dll4 and Notch4 enhancers•Notch signaling is required for maintenance, not specification, of arterial identity Vegf signaling specifies arterial fate via transcriptional induction of Delta-like 4 (Dll4), the earliest Notch ligand gene expressed in arterial precursor cells. Wythe et al. find that ETS transcription factors are activated downstream of Vegf/MAPK signaling to drive expression of Dll4 and the Notch receptor, Notch4, thereby establishing arterial identity.