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.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing
-
Animals
-
Animals, Genetically Modified / embryology
-
Animals, Genetically Modified / metabolism
-
Aorta / metabolism
-
Aorta / physiology*
-
Binding Sites
-
Calcium-Binding Proteins
-
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
Substances
-
Adaptor Proteins, Signal Transducing
-
Calcium-Binding Proteins
-
DLL4 protein, mouse
-
ERG protein, human
-
Intracellular Signaling Peptides and Proteins
-
Membrane Proteins
-
NOTCH4 protein, human
-
Proto-Oncogene Proteins
-
Receptor, Notch4
-
Receptors, Notch
-
Trans-Activators
-
Transcriptional Regulator ERG
-
Vascular Endothelial Growth Factor A
-
vascular endothelial growth factor A, mouse
-
Green Fluorescent Proteins