Publication: Analysis of Dll4 regulation reveals a combinatorial rolefor Sox and Notch in arterial development
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Date
2013-07-01
Authors
Sacilotto, Natalia ; Monteiro, Rui ; Fritzsche, Martin ; Becker, Philipp W. ; Sánchez del Campo Ferrer, Luis ; Liu, Ke ; Pinheiro, Philip ; Ratnayakaa, Indrika ; Davies, Benjamin ; Goding, Colin R. ; Patient, Roger ; Bou Gharios, George ; De Val, Sarah
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National Academy of Sciences
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Description
© 2013 National Academy of Sciences. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
This document is the Published version of a Published Work that appeared in final form in PNAS. To access the final edited and published work see https://doi.org/10.1073/pnas.1300805110
Abstract
The mechanisms by which arterial fate is established and main-tained are not clearly understood. Although a number of signalingpathways and transcriptional regulators have been implicated inarterio-venous differentiation, none are essential for arterialformation, and the manner in which widely expressed factorsmay achieve arterial-specific gene regulation is unclear. Using bothmouse and zebrafish models, we demonstrate here that arterialspecification is regulated combinatorially by Notch signaling andSoxF transcription factors, via direct transcriptional gene activa-tion. Through the identification and characterization of two arte-rial endothelial cell-specific gene enhancers for the Notch ligandDelta-like ligand 4 (Dll4), we show that arterial Dll4 expressionrequires the direct binding of both the RBPJ/Notch intracellulardomain and SOXF transcription factors. Specific combinatorial,but not individual, loss of SOXF and RBPJ DNA binding ablatesall Dll4 enhancer-transgene expression despite the presence ofmultiple functional ETS binding sites, as does knockdown of sox7;sox18 in combination with loss of Notch signaling. Furthermore,triple knockdown of sox7, sox18 and rbpj also results in ablationof endogenous dll4 expression. Fascinatingly, this combinatorialablation leads to a loss of arterial markers and the absence of a de-tectable dorsal aorta, demonstrating the essential roles of SoxF andNotch, together, in the acquisition of arterial identity
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