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

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dc.contributor.authorSacilotto, Natalia
dc.contributor.authorMonteiro, Rui
dc.contributor.authorFritzsche, Martin
dc.contributor.authorBecker, Philipp W.
dc.contributor.authorLiu, Ke
dc.contributor.authorPinheiro, Philip
dc.contributor.authorRatnayakaa, Indrika
dc.contributor.authorDavies, Benjamin
dc.contributor.authorGoding, Colin R.
dc.contributor.authorPatient, Roger
dc.contributor.authorBou Gharios, George
dc.contributor.authorDe Val, Sarah
dc.contributor.authorSánchez del Campo Ferrer, Luis
dc.contributor.departmentBioquímica y Biología Molecular Aes
dc.date.accessioned2024-12-10T09:08:37Z
dc.date.available2024-12-10T09:08:37Z
dc.date.issued2013-07-01
dc.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.1300805110es
dc.description.abstractThe 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 identityes
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dc.format.extent6es
dc.identifier.citationProceedings of the National Academy of Sciences (PNAS), 2013, Vol. 110, N. 29, pp. 11893–11898
dc.identifier.doihttps://doi.org/10.1073/pnas.1300805110
dc.identifier.issnElectronic: 1091-6490
dc.identifier.issnPrint: 0027-8424
dc.identifier.urihttp://hdl.handle.net/10201/147264
dc.languageenges
dc.publisherNational Academy of Scienceses
dc.relationLudwig Institute for Cancer Research, British Heart Foundation (BHF), BHF Centre of Research Excellence, Medical Research Council (MR/J007765/1)es
dc.relation.publisherversionhttps://www.pnas.org/doi/full/10.1073/pnas.1300805110es
dc.rightsinfo:eu-repo/semantics/openAccesses
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectArterial developmentes
dc.subjectDll4es
dc.subjectSoxes
dc.subjectNotches
dc.titleAnalysis of Dll4 regulation reveals a combinatorial rolefor Sox and Notch in arterial developmentes
dc.typeinfo:eu-repo/semantics/articlees
dspace.entity.typePublicationes
relation.isAuthorOfPublicationf702e5be-3f82-4512-b2a2-6c69a5cb98ff
relation.isAuthorOfPublication.latestForDiscoveryf702e5be-3f82-4512-b2a2-6c69a5cb98ff
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