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Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice.

Receptor tyrosine kinases Flt-1 and Flk-1/KDR, and their ligand, the vascular endothelial growth factor (VEGF), were shown to be essential for angiogenesis in the mouse embryo by gene targeting. Flk-1/KDR null mutant mice exhibited impaired endothelial and hematopoietic cell development. On the other hand, Flt-1 null mutation resulted in early embryonic death at embryonic day 8.5, showing disorganization of blood vessels, such as overgrowth of endothelial cells. Flt-1 differs from Flk-1 in that it displays a higher affinity for VEGF but lower kinase activity, suggesting the importance of its extracellular domain. To examine the biological role of Flt-1 in embryonic development and vascular formation, we deleted the kinase domain without affecting the ligand binding region. Flt-1 tyrosine kinase-deficient homozygous mice (flt-1(TK-/-)) developed normal vessels and survived. However, VEGF-induced macrophage migration was strongly suppressed in flt-1(TK-/-) mice. These results indicate that Flt-1 without tyrosine kinase domain is sufficient to allow embryonic development with normal angiogenesis, and that a receptor tyrosine kinase plays a main biological role as a ligand-binding molecule.

Pubmed ID: 9689083


  • Hiratsuka S
  • Minowa O
  • Kuno J
  • Noda T
  • Shibuya M


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

August 4, 1998

Associated Grants


Mesh Terms

  • Animals
  • Base Sequence
  • Capillary Permeability
  • Cells, Cultured
  • DNA Primers
  • Embryonic and Fetal Development
  • Endothelial Growth Factors
  • Endothelium, Vascular
  • Gene Targeting
  • Lymphokines
  • Macrophages
  • Mice
  • Neovascularization, Physiologic
  • Proto-Oncogene Proteins
  • Receptor Protein-Tyrosine Kinases
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor Receptor-1
  • Vascular Endothelial Growth Factors