Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice
- *Department of Genetics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; and †Department of Cell Biology, Cancer Institute, 1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo 170-0012, Japan
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Communicated by Hidesaburo Hanafusa, The Rockefeller University, New York, NY (received for review March 12, 1998)
Abstract
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-1TK−/−) developed normal vessels and survived. However, VEGF-induced macrophage migration was strongly suppressed in flt-1TK−/− 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.
ABBREVIATIONS
- VEGF,
- vascular endothelial growth factor;
- E,
- embryonic day;
- ES,
- embryonic stem
- Received March 12, 1998.
- Accepted June 12, 1998.
- Copyright © 1998, The National Academy of Sciences
