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Dev Cell. 2013 Jul 15;26(1):45-58. doi: 10.1016/j.devcel.2013.06.007. Epub 2013 Jul 3.

ETS factors regulate Vegf-dependent arterial specification.

Author information

1
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA. jwythe@gladstone.ucsf.edu

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.

PMID:
23830865
PMCID:
PMC3754838
DOI:
10.1016/j.devcel.2013.06.007
[Indexed for MEDLINE]
Free PMC Article

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