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Suppression of Notch signalling by the COUP-TFII transcription factor regulates vein identity


Arteries and veins are anatomically, functionally and molecularly distinct. The current model of arterial–venous identity proposes that binding of vascular endothelial growth factor to its heterodimeric receptor—Flk1 and neuropilin 1 (NP-1; also called Nrp1)—activates the Notch signalling pathway in the endothelium, causing induction of ephrin B2 expression and suppression of ephrin receptor B4 expression to establish arterial identity1,2,3,4. Little is known about vein identity except that it involves ephrin receptor B4 expression, because Notch signalling is not activated in veins; an unresolved question is how vein identity is regulated. Here, we show that COUP-TFII (also known as Nr2f2), a member of the orphan nuclear receptor superfamily, is specifically expressed in venous but not arterial endothelium. Ablation of COUP-TFII in endothelial cells enables veins to acquire arterial characteristics, including the expression of arterial markers NP-1 and Notch signalling molecules, and the generation of haematopoietic cell clusters. Furthermore, ectopic expression of COUP-TFII in endothelial cells results in the fusion of veins and arteries in transgenic mouse embryos. Thus, COUP-TFII has a critical role in repressing Notch signalling to maintain vein identity, which suggests that vein identity is under genetic control and is not derived by a default pathway.

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Figure 1: Differential expression pattern and chimaera analysis of COUP-TFII in the vasculature.
Figure 2: Arterial markers are ectopically expressed, whereas venous marker expression is reduced in veins of COUP-TFII mutant mice.
Figure 3: Ectopic formation of haematopoietic cell clusters in COUP-TFII mutant venous endothelium.
Figure 4: Mis-expression of COUP-TFII in the endothelium.
Figure 5: COUP-TFII maintains vein identity.


  1. Lawson, N. D. et al. Notch signaling is required for arterial-venous differentiation during embryonic vascular development. Development 128, 3675–3683 (2001)

    CAS  PubMed  Google Scholar 

  2. Gerety, S. S. & Anderson, D. J. Cardiovascular ephrinB2 function is essential for embryonic angiogenesis. Development 129, 1397–1410 (2002)

    CAS  PubMed  Google Scholar 

  3. Lawson, N. D., Vogel, A. M. & Weinstein, B. M. Sonic hedgehog and vascular endothelium growth factor act upstream of Notch pathway during arterial endothelial differentiation. Dev. Cell 3, 127–136 (2002)

    Article  CAS  PubMed  Google Scholar 

  4. Gu, C. et al. Neuropilin-1 conveys Semaphorin and VEGF signaling during neural and cardiovascular development. Dev. Cell 5, 45–57 (2003)

    Article  MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

  5. Pereira, F. A., Qiu, Y. H., Chou, G., Tsai, M.-J. & Tsai, S. Y. The orphan nuclear receptor COUP-TFII is required for angiogenesis and heart development. Genes Dev. 13, 1037–1049 (1999)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Takamoto, N. et al. COUP-TFII is essential for radial and anterior-posterior patterning of the stomach. Development 132, 2179–2182 (2005)

    Article  CAS  PubMed  Google Scholar 

  7. Sato, T. N. et al. Distinct roles of the receptor kinase Tie-1 and Tie-2 in blood vessel formation. Nature 376, 70–74 (1995)

    Article  ADS  CAS  PubMed  Google Scholar 

  8. Suri, C. et al. Requisite role of angiopoietin-1, a ligand for TIE2 receptor, during embryonic angiogenesis. Cell 87, 1171–1180 (1996)

    Article  CAS  PubMed  Google Scholar 

  9. Kisanuki, Y. Y. et al. Tie2-Cre transgenic mice: a new model for endothelial cell-lineage analysis in vivo . Dev. Biol. 230, 230–242 (2001)

    Article  CAS  PubMed  Google Scholar 

  10. Huppert, S. S. et al. Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1. Nature 405, 966–970 (2000)

    Article  ADS  CAS  PubMed  Google Scholar 

  11. Krebs, L. T. et al. Notch signaling is essential for vascular morphogenesis in mice. Genes Dev. 14, 1343–1352 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Xue, Y. et al. Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. Hum. Mol. Genet. 8, 723–730 (1999)

    Article  CAS  PubMed  Google Scholar 

  13. Villa, N. et al. Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels. Mech. Dev. 108, 161–164 (2001)

    Article  CAS  PubMed  Google Scholar 

  14. Wang, H. U., Chen, Z.-F. & Anderson, D. J. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93, 741–753 (1998)

    Article  CAS  PubMed  Google Scholar 

  15. Gerety, S. S., Wang, H. U., Chen, Z.-F. & Anderson, D. J. Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development. Mol. Cell 4, 403–414 (1999)

    Article  CAS  PubMed  Google Scholar 

  16. Shalaby, F. et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376, 62–66 (1995)

    Article  ADS  CAS  PubMed  Google Scholar 

  17. Kawasaki, T. et al. A requirement for neuropilin-1 in embryonic vessel formation. Development 126, 4895–4902 (1999)

    CAS  PubMed  Google Scholar 

  18. Zhong, T. P., Childs, S., Leu, J. P. & Fishman, M. C. Gridlock signalling pathway fashions the first embryonic artery. Nature 414, 216–220 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Fischer, A., Schumacher, N., Maier, M., Sendtner, M. & Gessler, M. The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes Dev. 18, 901–911 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Garcia-Porrero, J. A., Godin, I. E. & Dieterlen-lievre, F. Potential intraembryonic hemogenic sites at pre-liver stages in the mouse. Anat. Embryol. (Berl.) 192, 427–435 (1995)

    Article  Google Scholar 

  21. Tavian, M. et al. Aorta-associated CD34+ hematopoietic cells in the early human embryo. Blood 87, 67–72 (1996)

    CAS  PubMed  Google Scholar 

  22. Medvinsky, A. L., Samoylina, N. L., Muller, A. M. & Dzierzak, E. A. An early pre-liver intraembryonic source of CFU-S in the developing mouse. Nature 364, 64–67 (1993)

    Article  ADS  CAS  PubMed  Google Scholar 

  23. Godin, I. E., Garcia-Porrero, J. A., Coutinho, A., Dieterlen-lievre, F. & Macros, M. A. Para-aortic splanchnopleura from early mouse embryos contains B1a cell progenitors. Nature 364, 67–69 (1993)

    Article  ADS  CAS  PubMed  Google Scholar 

  24. Zhang, J. et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425, 836–841 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  25. Calvi, L. M. et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425, 841–846 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  26. Hogan, B. L. M., Beddington, R. S. P., Costantini, E. & Lacy, E. Manipulating the Mouse Embryo, a Laboratory Manual (Cold Spring Harbor Laboratory Press, New Yolk, 1994)

    Google Scholar 

  27. Adams, R. H. Molecular control of arterial-venous blood vessel identity. J. Anat. 202, 105–112 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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We thank W. Qian and C. Yang for technical assistance; M. Yanagisawa for providing the Tie2-Cre transgenic mice; Y. Furuta for providing the Efnb2 construct for RNA in situ hybridization; and F. Petit for the COUP-TFII minigene construct. We also thank L.-Y. Yu-Lee and H. J. Bellen for discussions and critical reading of the manuscript. This work was supported by NIH grants to S.Y.T. and M.-J.T.

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Correspondence to Ming-Jer Tsai or Sophia Y. Tsai.

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Supplementary information

Supplementary Figure S1

Differential expression pattern of COUP-TFII using knockin lacZ reporter as a marker in the vasculature. (PDF 158 kb)

Supplementary Figure S2

Model of cell autonomous versus non-cell autonomous functions. (PDF 50 kb)

Supplementary Figure S3

Endothelial-specific knockout of COUP-TFII by Tie2-Cre. (PDF 125 kb)

Supplementary Figure S4

The endothelial-specific COUP-TFII null mutants exhibited a variety of vascular defects. (PDF 138 kb)

Supplementary Figure S5

The haematopoietic-specific markers in haematopoietic cell clusters of the mutant. (PDF 99 kb)

Supplementary Figure Legends

Legends to accompany the above Supplementary Figures. (DOC 25 kb)

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You, LR., Lin, FJ., Lee, C. et al. Suppression of Notch signalling by the COUP-TFII transcription factor regulates vein identity. Nature 435, 98–104 (2005).

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