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Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene

Nature volume 380, pages 439–442 (1996)Cite this article

Abstract

ANGIOGENESIS is required for a wide variety of physiological and pathological processes1. The endothelial cell-specific mitogen vascular endothelial growth factor (VEGF)2,3 is a major mediator of pathological angiogenesis4–6. Also, the expression of VEGF and its two receptors, Flt-1 and Flk-1/KDR, is related to the formation of blood vessels in mouse and rat embryos7–10. Mice homozygous for mutations that inactivate either receptor die in utero between days 8.5 and 9.5 (refs 11,12). However, ligand(s) other than VEGF might activate such receptors13,14. To assess the role of VEGF directly, we disrupted the VEGF gene in embryonic stem cells. Here we report the unexpected finding that loss of a single VEGF allele is lethal in the mouse embryo between days 11 and 12. Angiogenesis and blood-island formation were impaired, resulting in several developmental anomalies. Furthermore, VEGF-null embryonic stem cells exhibit a dramatically reduced ability to form tumours in nude mice.

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References

  1. Folkman, J. & Shing, Y. J. biol. Chem. 267, 10931–10934 (1992).

    CAS  Google Scholar 

  2. Ferrara, N., Houck, K., Jakeman, L. & Leung, D. W. Endocr. Rev. 13, 18–32 (1992).

    CAS  Article  Google Scholar 

  3. Dvorak, H. F., Brown, L. F., Detmar, M. & Dvorak, A. M. Am. J. Path. 146, 1029–1039 (1995).

    CAS  PubMed  Google Scholar 

  4. Kim, K. J. et al. Nature 362, 841–844 (1993).

    ADS  CAS  Article  Google Scholar 

  5. Adamis, A. P. et al. Am. J. Ophthalmol. 118, 445–450 (1994).

    CAS  Article  Google Scholar 

  6. Aiello, L. P. et al. New Engl. J. Med. 331, 1480–1487 (1994).

    CAS  Article  Google Scholar 

  7. Breier, G., Albrecht, U., Sterrer, S. & Risau, W. Development 114, 521–532 (1992).

    CAS  Google Scholar 

  8. Jakeman, L. B., Armanini, M., Phillips, H. S. & Ferrara, N. Endocrinology 133, 848–859 (1993).

    CAS  Article  Google Scholar 

  9. Quinn, T., Peters, K. G., deVries, C., Ferrara, N. & Williams, L. T. Proc. natn. Acad. Sci. U.S.A. 90, 7533–7537 (1993).

    ADS  CAS  Article  Google Scholar 

  10. Peters, K. G., deVries, C. & Williams, L. T. Proc. natn. Acad. Sci. U.S.A. 90, 8915–8919 (1993).

    ADS  CAS  Article  Google Scholar 

  11. Fong, G.-H., Rossant, J., Gertenstein, M. & Breitman, M. Nature 376, 66–70 (1995).

    ADS  CAS  Article  Google Scholar 

  12. Shalabi, F. et al. Nature 376, 62–66 (1995).

    ADS  Article  Google Scholar 

  13. Park, J. E., Chen, H., Winer, J., Houck, K. A. & Ferrara, N. J. biol. Chem. 269, 25646–25654 (1994).

    CAS  Google Scholar 

  14. Maglione, D., Guerriero, V., Viglietto, G., Delli-Bovi, P. & Persico, M. G. Proc. natn. Acad. Sci. U.S.A. 88, 9267–9271 (1991).

    ADS  CAS  Article  Google Scholar 

  15. Tisher, E. et al. J. biol. Chem. 266, 11947–11954 (1991).

    Google Scholar 

  16. Tybulewicz, V. L. J., Crawford, C. E., Jackson, P. K., Bronson, R. T. & Mulligan, R. C. Cell 65, 1153–1163 (1991).

    CAS  Article  Google Scholar 

  17. Vigon, I. M. et al. Proc. natn. Acad. Sci. U.S.A. 89, 5640–5644 (1992).

    ADS  CAS  Article  Google Scholar 

  18. Risau, W. et al. Development 102, 471–478 (1988).

    CAS  Google Scholar 

  19. Hilberg, F. & Wagner, E. F. Oncogene 7, 2371–2380 (1992).

    CAS  Google Scholar 

  20. Pugh, R. B. C. Pathology of the Testis (Blackwell, Oxford, 1976).

    Google Scholar 

  21. Hogan, B., Beddington, R., Constantini, F. & Lacy, E. Manipulating the Mouse Embryo 2nd edn (Cold Spring Harbor Laboratory Press, NY, 1994).

    Google Scholar 

  22. Bradley, A. in Teratocarcinoma and Embryonic Stem Cells: A Practical Approach (ed. Robertson, E. G.) 113–152 (ERL, Oxford, 1987).

    Google Scholar 

  23. Theiler, K. The House Mouse. Atlas of Embryonic Development (Springer, New York, 1989).

    Book  Google Scholar 

  24. Brandon, E. P., Idzerda, R. L. & McKnight, G. S. Curr. Biol. 5, 625–634 (1995).

    CAS  Article  Google Scholar 

  25. McBride, W. G. Lancet ii, 1358–1364 (1987).

    Google Scholar 

  26. D'Amato, R. J., Loughnan, M. S., Flynn, E. & Folkman, J. Proc. natn. Acad. Sci. U.S.A. 91, 4082–4085 (1994).

    ADS  CAS  Article  Google Scholar 

  27. Sambrook, J., Fritsch, E. F. & Maniatis, T. Molecular Cloning, a Laboratory Manual 2nd edn (Cold Spring Harbor Laboratory Press, NY, 1989).

    Google Scholar 

  28. Mansour, S. L., Thomas, K. R. & Capecchi, M. R. Nature 336, 348–352 (1988).

    ADS  CAS  Article  Google Scholar 

  29. Mortensen, R. M., Conner, D. A., Chao, S., Geisterfer-Lowrance, A. A. & Seldman, J. G. Molec. cell. Biol. 12, 2391–2395 (1992).

    CAS  Article  Google Scholar 

  30. Lu, L. H. & Gillett, N. Cell Vision 1, 169–176 (1994).

    CAS  Google Scholar 

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Author notes

  1. K. Sue O'Shea: Department of Anatomy and Cell Biology, University of Michigan, Ann Arbor, Michigan 48109, USA

Affiliations

  1. Departments of Cardiovascular Research, Molecular Biology and Bioanalytical Technology, Genentech Inc., 460 Point San Bruno Boulevard, South San Francisco, California, 94080, USA

    Napoleone Ferrara, Karen Carver-Moore, Helen Chen, Mary Dowd, Lucy Lu, K. Sue O'Shea, Lyn Powell-Braxton, Kenneth J. Hillan & Mark W. Moore

Authors
  1. Napoleone Ferrara
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  2. Karen Carver-Moore
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  3. Helen Chen
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  4. Mary Dowd
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  5. Lucy Lu
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  6. K. Sue O'Shea
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  7. Lyn Powell-Braxton
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  8. Kenneth J. Hillan
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  9. Mark W. Moore
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Ferrara, N., Carver-Moore, K., Chen, H. et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380, 439–442 (1996). https://doi.org/10.1038/380439a0

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