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Control of endothelial sprouting by a Tel–CtBP complex

Nature Cell Biology volume 12, pages 933–942 (2010)Cite this article

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Abstract

We show that the transcriptional repressor Tel plays an evolutionarily conserved role in angiogenesis: it is indispensable for the sprouting of human endothelial cells and for normal development of the Danio rerio blood circulatory system. Tel orchestrates endothelial sprouting by binding to the generic co-repressor, CtBP. The Tel–CtBP complex temporally restricts a VEGF (vascular endothelial growth factor)-mediated pulse of dll4 expression and thereby directly links VEGF receptor intracellular signalling and intercellular Notch–Dll4 signalling. It further controls branching by regulating expression of other factors that constrain angiogenesis such as sprouty family members and ve-cadherin. Thus, the Tel–CtBP complex conditions endothelial cells for angiogenesis by controlling the balance between stimulatory and antagonistic sprouting cues. Tel control of branching seems to be a refinement of invertebrate tracheae morphogenesis that requires Yan, the invertebrate orthologue of Tel. This work highlights Tel and its associated networks as potential targets for the development of therapeutic strategies to inhibit pathological angiogenesis.

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Figure 1: Tel is essential for endothelial sprouting.
Figure 2: Tel associates with CtBP through a conserved consensus-binding motif.
Figure 3: The N terminus of CtBP2 reinforces stable interactions between CtBP2 and Tel.
Figure 4: CtBP regulates Tel stability and subcellular localization.
Figure 5: Tel control of endothelial sprouting requires CtBP.
Figure 6: Tel primes endothelial sprouting by inhibiting expression of sprouting antagonists.
Figure 7: Tel and CtBP2 are required for zebrafish embryo angiogenesis.

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Acknowledgements

We thank members of the Department of Molecular Cell Biology and the Schulte-Merker laboratory for helpful discussions. We would particularly like to thank P. Meier, P. ten Dijke, E. Meulmeester and M. Goncalves for critical reading of the manuscript. We are indebted to G. Chinnadurai for the human CtBP plasmids, S. Parkhurst for the Drosophila CtBP plasmid and antibody and Genentech for providing their neutralizing anti-Dll4 antibody16. We thank E. Bos for assistance with the culture of HUVECs and L. Hawinkels for providing primary tumour sections and, together with L. Pardali, for advice on the immunohistochemistry experiments. We are indebted to F. Bos for help and advice with microscopy. We are grateful to J. Oosting for the analyses of the microarray data and A. van der Laan for help with the confocal microscopy.

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Authors and Affiliations

  1. Department of Molecular Cell Biology, Leiden University Medical Center (LUMC), Section of Growth Control and Transcription, Leiden, 2300 RC, The Netherlands

    M. Guy Roukens, Mariam Alloul-Ramdhani & David A. Baker

  2. Department of Molecular Cell Biology, Leiden University Medical Center (LUMC), Section of Signal Transduction, Leiden, 2300 RC, The Netherlands

    Bart Baan, Kazuki Kobayashi & Hans van Dam

  3. Hubrecht Institute-KNAW & University Medical Centre, Utrecht, 3584 CT, The Netherlands

    Josi Peterson-Maduro & Stefan Schulte-Merker

  4. Centre for Biomedical Genetics, Uppsalalaan 8, Utrecht, 3584 CT, The Netherlands

    Josi Peterson-Maduro & Stefan Schulte-Merker

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Contributions

M.G.R. performed most of the experiments assisted by M.A.R. and D.A.B. B.B. performed PLA experiments assisted by H. v.D. K.K. isolated and cultured fresh primary HUVECs. J. P.-M. and S. S.-M. helped design and perform experiments described in Figure 7. S. S.-M. provided reagents, essential technical expertise and intellectual input. D.A.B. conceived the project, designed the experiments with M.G.R. and wrote the paper assisted by M.G.R.

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Correspondence to David A. Baker.

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Roukens, M., Alloul-Ramdhani, M., Baan, B. et al. Control of endothelial sprouting by a Tel–CtBP complex. Nat Cell Biol 12, 933–942 (2010). https://doi.org/10.1038/ncb2096

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