期刊
DEVELOPMENTAL CELL
卷 26, 期 1, 页码 45-58出版社
CELL PRESS
DOI: 10.1016/j.devcel.2013.06.007
关键词
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资金
- American Heart Association [12SDG12060353]
- National Institutes of Health (NIH) [5T32-HL007544, 5T32-HL007731-20, PO1 HL76540, HL54737]
- California Institute of Regenerative Medicine [TG2-01160]
- Packard Foundation
- NHLBI [P01 HL089707, HL64658]
- Canadian Institutes of Health Research [MOP-119506]
- Ontario Ministry of Economic Development and Innovation
- Canada Foundation for Innovation
- Heart and Stroke Foundation of Canada
- American Heart Association, Western States Affiliate [12PILT12670005]
- Lawrence J. and Florence A. DeGeorge Charitable Trust/American Heart Association
- NIH/NCRR [C06 RR018928]
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.
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