title: ETS factors regulate Vegf-dependent arterial specification.
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.
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA. jwythe@gladstone.ucsf.edu
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Wythe
authors.forename: Lan T H
authors.initials: LT
authors.lastname: Dang
authors.forename: W Patrick
authors.initials: WP
authors.lastname: Devine
authors.forename: Emilie
authors.initials: E
authors.lastname: Boudreau
authors.forename: Stanley T
authors.initials: ST
authors.lastname: Artap
authors.forename: Daniel
authors.initials: D
authors.lastname: He
authors.forename: William
authors.initials: W
authors.lastname: Schachterle
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
authors.forename: Peter
authors.initials: P
authors.lastname: Oettgen
authors.forename: Brian L
authors.initials: BL
authors.lastname: Black
authors.forename: Benoit G
authors.initials: BG
authors.lastname: Bruneau
authors.forename: Jason E
authors.initials: JE
authors.lastname: Fish
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D030801:Animals, Genetically Modified / Q000196:embryology / Q000378:metabolism; D001011:Aorta / Q000378:metabolism / Q000502:physiology*; D001665:Binding Sites; D002135:Calcium-Binding Proteins; D004699:Endocardium / Q000196:embryology / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009928:Organ Specificity; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D000071230:Transcriptional Regulator ERG; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; C072312:ERG protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D000074562:Receptor, Notch4; D051880:Receptors, Notch; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D049452:Green Fluorescent Proteins