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Cited by 77Lymphatic System and DiseasesDevelopmental Biology and Gene RegulationAngiogenesis and VEGF in Cancer

COUP-TFII orchestrates venous and lymphatic endothelial identity by homo- or hetero-dimerisation with PROX1

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Aranguren, Xabier L., Beerens, Manu, Coppiello, Giulia, Wiese, Cornelia, Vandersmissen, Ine, Lo Nigro, Antonio, Verfaillie, Catherine M., Gessler, Manfred +1 more·2013·Journal of Cell Science
DOI 10.1242/jcs.116293
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Abstract

Summary: Endothelial cell (EC) identity is in part genetically predetermined. Transcription factor NR2F2 (also known as chicken ovalbumin upstream promoter transcription factor II, COUP-TFII) plays a key role in EC fate decision making; however, many of the underlying mechanisms remain enigmatic. In the present study, we demonstrate that NR2F2 differentially regulates gene expression of venous versus lymphatic ECs (LECs) and document a novel paradigm whereby NR2F2 homodimers induce a venous EC fate, while heterodimers with the LEC-specific transcription factor PROX1 instruct LEC lineage specification. NR2F2 homodimers inhibit arterial differentiation in venous ECs through direct binding to the promoter regions of the Notch target genes HEY1 and HEY2 (HEY1/2), whereas NR2F2/PROX1 heterodimers lack this inhibitory effect, resulting at least in part in non-canonical HEY1/2 expression in LECs. Furthermore, NR2F2/PROX1 heterodimers actively induce or are permissive for the expression of a major subset of LEC-specific genes. In addition to NR2F2/PROX1 heterodimerisation, the expression of HEY1 and some of these LEC-specific genes is dependent on PROX1 DNA binding. Thus, NR2F2 homodimers in venous ECs and NR2F2/PROX1 heterodimers in LECs differentially regulate EC subtype-specific genes and pathways, most prominently the Notch target genes HEY1/2. This novel mechanistic insight could pave the way for new therapeutic interventions for vascular-bed-specific disorders.

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  • In hepatocytes, corepressor interactions are reported.

    “Conversely, in hepatocytes, corepressor interactions are reported43–45, and we found that PROX1 interacted with the repressive NuRD complex in the liver but not in the brain.”

    From Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis (2025) · cites this paper as [43]

    The section on NR2F2 homo- and heterodimerisation reports PROX1 interactions in lymphatic endothelial cells, not hepatocytes. Searches for hepatocytes, liver, corepressors, and NuRD found no passage in our copy reporting the hepatocyte corepressor interactions attributed to this paper. (LLM, conf=0.76)

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Authors
Aranguren, X. L., Beerens, M., Coppiello, G., Wiese, C., Vandersmissen, I., Lo Nigro, A., Verfaillie, C. M., Gessler, M., & Luttun, A.
Affiliations
  • KU Leuven (BE)
  • University of Würzburg (DE)
  • Stem Cell Institute Leuven, KU Leuven, B-3000 Leuven, Belgium
  • Leuven Stem Cell Institute (BE)
Corresponding author
Luttun, Aernout
ORCID
Venue
Journal of Cell Science
Publisher
The Company of Biologists
Published
2013-03-01
Volume
126
Issue
5
Pages
1164-1175
ISSN
  • 0021-9533 (ISSN-L)
  • 1477-9137
DOI
10.1242/jcs.116293
OpenAlex
W2131785738
Cited by
77
References
43
Citations by year
2026: 4 · 2025: 6 · 2024: 4 · 2023: 3 · 2022: 4 · 2021: 9 · 2020: 4 · 2019: 6 · 2018: 6 · 2017: 4 · 2016: 5 · 2015: 7 · 2014: 12 · 2013: 3
FWCI
4.82
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • Journal of Cell Science (publishedVersion)
  • PubMed (publishedVersion)
  • Lirias (KU Leuven) (submittedVersion)
  • Lirias (submittedVersion, other-oa)
Funders
  • Lymphatic Research Foundation
  • European Commission (FP7-StG-IMAGINED 203291)
  • Deutsche Forschungsgemeinschaft (TPA16)
  • Fonds Wetenschappelijk Onderzoek (GOA11/012)
  • Agentschap voor Innovatie door Wetenschap en Technologie
  • KU Leuven (PF/10/014, 10/014, EF/05/013, GOA11/012)
Topics
  • Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Keywords
COUP-TFII, NR2F2, Prox1, lymphatic endothelial cells, venous endothelial cells, transcription factor dimerization, Hey1, Hey2, Notch signaling, transcriptional regulation
MeSH terms
Prospero-Related Homeobox 1 Protein, Cell Line, Cells, Cultured, Endothelium, Vascular, Humans, Repressor Proteins, Veins, Blotting, Western, Homeodomain Proteins, Cell Cycle Proteins, Tumor Suppressor Proteins, Lymphatic Vessels, Chromatin Immunoprecipitation, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, COUP Transcription Factor II, Protein Multimerization, Real-Time Polymerase Chain Reaction

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