Analysis of Dll4 regulation reveals a combinatorial role for Sox and Notch in arterial development

Research output: Contribution to journalArticle

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Analysis of Dll4 regulation reveals a combinatorial role for Sox and Notch in arterial development. / Sacilotto, Natalia; Monteiro, Rui; Fritzsche, Martin; Becker, Philipp W.; Sanchez-del-Campo, Luis; Liu, Ke; Pinheiro, Philip; Ratnayaka, Indrika; Davies, Benjamin; Goding, Colin R.; Patient, Roger; Bou-Gharios, George; De Val, Sarah.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 29, 16.07.2013, p. 11893-11898.

Research output: Contribution to journalArticle

Harvard

Sacilotto, N, Monteiro, R, Fritzsche, M, Becker, PW, Sanchez-del-Campo, L, Liu, K, Pinheiro, P, Ratnayaka, I, Davies, B, Goding, CR, Patient, R, Bou-Gharios, G & De Val, S 2013, 'Analysis of Dll4 regulation reveals a combinatorial role for Sox and Notch in arterial development', Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 29, pp. 11893-11898. https://doi.org/10.1073/pnas.1300805110

APA

Sacilotto, N., Monteiro, R., Fritzsche, M., Becker, P. W., Sanchez-del-Campo, L., Liu, K., Pinheiro, P., Ratnayaka, I., Davies, B., Goding, C. R., Patient, R., Bou-Gharios, G., & De Val, S. (2013). Analysis of Dll4 regulation reveals a combinatorial role for Sox and Notch in arterial development. Proceedings of the National Academy of Sciences of the United States of America, 110(29), 11893-11898. https://doi.org/10.1073/pnas.1300805110

Vancouver

Author

Sacilotto, Natalia ; Monteiro, Rui ; Fritzsche, Martin ; Becker, Philipp W. ; Sanchez-del-Campo, Luis ; Liu, Ke ; Pinheiro, Philip ; Ratnayaka, Indrika ; Davies, Benjamin ; Goding, Colin R. ; Patient, Roger ; Bou-Gharios, George ; De Val, Sarah. / Analysis of Dll4 regulation reveals a combinatorial role for Sox and Notch in arterial development. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 29. pp. 11893-11898.

Bibtex

@article{ce7a37060844457dbc99879e49a76931,
title = "Analysis of Dll4 regulation reveals a combinatorial role for Sox and Notch in arterial development",
abstract = "The mechanisms by which arterial fate is established and maintained are not clearly understood. Although a number of signaling pathways and transcriptional regulators have been implicated in arterio-venous differentiation, none are essential for arterial formation, and the manner in which widely expressed factors may achieve arterial-specific gene regulation is unclear. Using both mouse and zebrafish models, we demonstrate here that arterial specification is regulated combinatorially by Notch signaling and SoxF transcription factors, via direct transcriptional gene activation. Through the identification and characterization of two arterial endothelial cell-specific gene enhancers for the Notch ligand Delta-like ligand 4 (Dll4), we show that arterial Dll4 expression requires the direct binding of both the RBPJ/Notch intracellular domain and SOXF transcription factors. Specific combinatorial, but not individual, loss of SOXF and RBPJ DNA binding ablates all Dll4 enhancer-transgene expression despite the presence of multiple 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 ablation of endogenous dll4 expression. Fascinatingly, this combinatorial ablation leads to a loss of arterial markers and the absence of a detectable dorsal aorta, demonstrating the essential roles of SoxF and Notch, together, in the acquisition of arterial identity.",
keywords = "Arterial-Specific Enhancer, Csl",
author = "Natalia Sacilotto and Rui Monteiro and Martin Fritzsche and Becker, {Philipp W.} and Luis Sanchez-del-Campo and Ke Liu and Philip Pinheiro and Indrika Ratnayaka and Benjamin Davies and Goding, {Colin R.} and Roger Patient and George Bou-Gharios and {De Val}, Sarah",
year = "2013",
month = jul,
day = "16",
doi = "10.1073/pnas.1300805110",
language = "English",
volume = "110",
pages = "11893--11898",
journal = "National Academy of Sciences. Proceedings",
issn = "1091-6490",
publisher = "National Academy of Sciences",
number = "29",

}

RIS

TY - JOUR

T1 - Analysis of Dll4 regulation reveals a combinatorial role for Sox and Notch in arterial development

AU - Sacilotto, Natalia

AU - Monteiro, Rui

AU - Fritzsche, Martin

AU - Becker, Philipp W.

AU - Sanchez-del-Campo, Luis

AU - Liu, Ke

AU - Pinheiro, Philip

AU - Ratnayaka, Indrika

AU - Davies, Benjamin

AU - Goding, Colin R.

AU - Patient, Roger

AU - Bou-Gharios, George

AU - De Val, Sarah

PY - 2013/7/16

Y1 - 2013/7/16

N2 - The mechanisms by which arterial fate is established and maintained are not clearly understood. Although a number of signaling pathways and transcriptional regulators have been implicated in arterio-venous differentiation, none are essential for arterial formation, and the manner in which widely expressed factors may achieve arterial-specific gene regulation is unclear. Using both mouse and zebrafish models, we demonstrate here that arterial specification is regulated combinatorially by Notch signaling and SoxF transcription factors, via direct transcriptional gene activation. Through the identification and characterization of two arterial endothelial cell-specific gene enhancers for the Notch ligand Delta-like ligand 4 (Dll4), we show that arterial Dll4 expression requires the direct binding of both the RBPJ/Notch intracellular domain and SOXF transcription factors. Specific combinatorial, but not individual, loss of SOXF and RBPJ DNA binding ablates all Dll4 enhancer-transgene expression despite the presence of multiple 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 ablation of endogenous dll4 expression. Fascinatingly, this combinatorial ablation leads to a loss of arterial markers and the absence of a detectable dorsal aorta, demonstrating the essential roles of SoxF and Notch, together, in the acquisition of arterial identity.

AB - The mechanisms by which arterial fate is established and maintained are not clearly understood. Although a number of signaling pathways and transcriptional regulators have been implicated in arterio-venous differentiation, none are essential for arterial formation, and the manner in which widely expressed factors may achieve arterial-specific gene regulation is unclear. Using both mouse and zebrafish models, we demonstrate here that arterial specification is regulated combinatorially by Notch signaling and SoxF transcription factors, via direct transcriptional gene activation. Through the identification and characterization of two arterial endothelial cell-specific gene enhancers for the Notch ligand Delta-like ligand 4 (Dll4), we show that arterial Dll4 expression requires the direct binding of both the RBPJ/Notch intracellular domain and SOXF transcription factors. Specific combinatorial, but not individual, loss of SOXF and RBPJ DNA binding ablates all Dll4 enhancer-transgene expression despite the presence of multiple 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 ablation of endogenous dll4 expression. Fascinatingly, this combinatorial ablation leads to a loss of arterial markers and the absence of a detectable dorsal aorta, demonstrating the essential roles of SoxF and Notch, together, in the acquisition of arterial identity.

KW - Arterial-Specific Enhancer

KW - Csl

UR - http://www.scopus.com/inward/record.url?scp=84880356030&partnerID=8YFLogxK

U2 - 10.1073/pnas.1300805110

DO - 10.1073/pnas.1300805110

M3 - Article

C2 - 23818617

AN - SCOPUS:84880356030

VL - 110

SP - 11893

EP - 11898

JO - National Academy of Sciences. Proceedings

JF - National Academy of Sciences. Proceedings

SN - 1091-6490

IS - 29

ER -