FAILURE OF BLOOD-ISLAND FORMATION AND VASCULOGENESIS IN FLK-1-DEFICIENT MICE

THE receptor tyrosine kinase Flk-1 (ref. 1) is believed to play a pivo tal role in endothelial development. Expression of the Flk-1 receptor is restricted to endothelial cells and their embryonic precursors(2-5) , and is complementary to that of its ligand, vascular endothelial gro wth factor (VEGF)(2,3), which, is aa endothelial-specific mitogen. Hig hest levels of flk-1 expression are observed during embryonic vasculog enesis and angiogenesis(2-5), and dating pathological processes associ ated with neovascularization, such its tumour angiogenesis(7,8). Becau se flk-1 expression can be detected in presumptive mesodermal yolk-sac blood-island progenitors as early as 7.0 days postcoitum, Flk-1 may m ark the putative common embryonic endothelial and haematopoietic precu rsor, the haemangioblast, and thus may also be involved in early haema topoiesis(4). Here rye report the generation of mice deficient in Flk- 1 by disruption of the gene using homologous recombination in embryoni c stem (ES) cells. Embryos homozygous for this mutation die in utero b etween 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 blo od islands were absent at 7.5 days, organized blood vessels could not be observed in the embryo or yolk sac at any stage, acid haematopoieti c progenitors were severely reduced. These results indicate that Flk-1 is essential for yolk-sac Mood-island formation and vasculogenesis in the mouse embryo.