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Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice

Abstract

THE receptor tyrosine kinase Flk-1 (ref. 1) is believed to play a pivotal role in endothelial development. Expression of the Flk-1 receptor is restricted to endothelial cells and their embryonic precursors2–5, and is complementary to that of its ligand, vascular endothelial growth factor (VEGF)2,3, which is an endothelial-speci-fic mitogen6. Highest levels of flk-1 expression are observed during embryonic vasculogenesis and angiogenesis2–5, and during pathological processes associated with neovascularization, such as tumour angiogenesis7,8. Because flk-1 expression can be detected in presumptive mesodermal yolk-sac blood-island progenitors as early as 7.0 days postcoitum, Flk-1 may mark the putative common embryonic endothelial and haematopoietic precursor, the haemangioblast, and thus may also be involved in early haematopoiesis4. Here we report the generation of mice deficient in Flk-1 by disruption of the gene using homologous recombination in embryonic stem (ES) cells. Embryos homozygous for this mutation die in utero between 8.5 and 9.5 days post-coitum, as a result of an early defect in the development of haematopoietic and endothelial cells. Yolk-sac blood islands were absent at 7.5 days, organized blood vessels could not be observed in the embryo or yolk sac at any stage, and haematopoietic progenitors were severely reduced. These results indicate that Flk-1 is essential for yolk-sac blood-island formation and vasculogenesis in the mouse embryo.

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References

  1. Mathews, W. et al. Proc. natn. Acad. Sci. U.S.A. 88, 9026–9030 (1991).

    Article  ADS  Google Scholar 

  2. Millauer, B. et al. Cell, 72, 1–12 (1993).

    Article  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  4. Yamaguchi, T. P., Dumont, D. J., Conlon, R. A., Breitman, M. L. & Rossant, J. Development 118, 489–498 (1993).

    CAS  Google Scholar 

  5. Oelrichs, R. B., Hugh, R. H., Bernard, O., Ziemiecki, A. & Wilks, A. F. Oncogene 8, 11–15 (1993).

    CAS  Google Scholar 

  6. Ferrara, N. & Henzel, W. J. Biochem. biophys. Res. Commun. 161, 851–858 (1989).

    Article  CAS  Google Scholar 

  7. Plate, K. H., Breier, G., Millauer, B., Ullrich, A. & Risau, W. Cancer Res. 53, 5822–5827 (1993).

    CAS  Google Scholar 

  8. Millauer, B., Shawver, L. K., Plate, K. H., Risau, W. & Ullrich, A. Nature 367, 576–579 (1994).

    Article  ADS  CAS  Google Scholar 

  9. Kaipainen, A. et al. Proc. natn. Acad. Sci. U.S.A. (in the press).

  10. Dumont, D. J., Yamaguchi, T. P., Conlon, R. A., Rossant, J. & Breitman, M. L. Oncogene 7, 1471–1480 (1992).

    CAS  PubMed  Google Scholar 

  11. Dumont, D. J. et al. Devl Dynam. 203, 80–92 (1995).

    Article  CAS  Google Scholar 

  12. Korhonen, J., Polvi, A., Partanen, J. & Alitalo, K. Oncogene 9, 395–403 (1994).

    CAS  Google Scholar 

  13. Brotherton, T. W., Chui, D. H., Gauldie, J. & Patterson, M. Proc. natn. Acad. Sci. U.S.A. 76, 2853–2857 (1979).

    Article  ADS  CAS  Google Scholar 

  14. Tsai, F. et al. Nature 339, 446–451 (1989).

    Article  ADS  CAS  Google Scholar 

  15. Weiss, M. J., Keller, G. & Orkin, S. H. Genes Dev. 8, 1184–1197 (1994).

    Article  CAS  Google Scholar 

  16. Zipori, D. & Lee, F. Blood 71, 586–596 (1988).

    CAS  PubMed  Google Scholar 

  17. Young, P. E., Baumhueter, S. & Lasky, L. A. Blood 85, 96–101 (1995).

    CAS  PubMed  Google Scholar 

  18. Noden, D. M. Am. Rev. resp. Dis. 140, 1097–1103 (1989).

    Article  CAS  Google Scholar 

  19. Medvinsky, A. L., Samoylina, N. L., Muller, A. M. & Dziersak, E. A. Nature 364, 64–67 (1993).

    Article  ADS  CAS  Google Scholar 

  20. Godin, I. E., Garcia-Porrero, J. A., Coutinho, A., Dieterlen-Lievre, F. & Marcos, M. A. R. Nature 364, 67–70 (1993).

    Article  ADS  CAS  Google Scholar 

  21. Wagner, R. C. Adv. Microcirc. 9, 45–75 (1980).

    Google Scholar 

  22. Shibuya, M. et al. Oncogene 5, 519–524 (1990).

    CAS  Google Scholar 

  23. Fong, G.-H., Rossant, J., Gertsenstein, M. & Breitman, M. L. Nature 376, 66–70 (1995).

    Article  ADS  CAS  Google Scholar 

  24. Wong, P. M., Chung, S. W., Chui, C. H. & Eaves, C. J. Proc. natn. Acad. Sci. U.S.A. 83, 3851–3854 (1986).

    Article  ADS  CAS  Google Scholar 

  25. Sambrook, J., Fritsch, E. F. & Maniatis, T. Molecular Cloning, a Laboratory Manual 2nd edn (Cold Spring Harbour Laboratory Press, New York, 1989).

    Google Scholar 

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

    Article  CAS  Google Scholar 

  27. Nagy, A., Rossant, J., Nagy, R., Abramow-Newerly, W. & Roder, J. C. Proc. natn. Acad. Sci. U.S.A. 90, 8424–8428 (1993).

    Article  ADS  CAS  Google Scholar 

  28. Wurst, W. & Joyner, A. L. in Gene Targeting 33–61 (Oxford Univ. Press, New York, 1993).

    Google Scholar 

  29. Iwama, A. et al. Biochem. biophys. Res. Commun. 195, 301–309 (1993).

    Article  CAS  Google Scholar 

  30. Keller, G., Kennedy, M., Papayannopoulou, T. & Wiles, M. Molec. cell. Biol. 13, 473–486 (1993).

    Article  CAS  Google Scholar 

  31. McClanahan, T., Dalrymple, S., Barkett, M. & Lee, F. Blood 81, 2903–2915 (1993).

    CAS  PubMed  Google Scholar 

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Shalaby, F., Rossant, J., Yamaguchi, T. et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376, 62–66 (1995). https://doi.org/10.1038/376062a0

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