Essential role of Flk-1 (VEGF receptor 2) tyrosine residue 1173 in vasculogenesis in mice

Flk-1 (human counterpart, KDR) tyrosine kinase, which is one of the two VEGF receptors, is crucial for vascular development. Recently, we showed that, among tyrosine residues of KDR, tyrosine residues 1175 (Y1 175, corresponding to Y1 173 in murine Flk-1) and Y1 214 (Y1 212 in Flk-1) are autophosphorylated in response to VEGF, and that Y1 175 is important for VEGF-dependent phospholipase Cy/PKC/mitogen-activated protein kinase activation leading to DNA synthesis in cultured endothelial cells. However, the importance of these tyrosine residues in Flk-1/KDR in vivo is not yet known. To examine the role of these Flk-1 tyrosine residues in vivo, we generated knock-in mice substituting Y1 173 and Y1 212 of the Flk-1 gene with phenylalanine, respectively. As a result, Flk-11173F homozygous mice died between embryonic days 8.5 and 9.5 without any organized blood vessels or yolk sac blood islands, and hematopoietic progenitors were severely reduced, similar to the case of Flk-1 null mice. In contrast, Flk-11212F homozygous mice were viable and fertile. These results suggest that the signaling via Y1173 of Flk-1 is essential for endothelial and hematopoietic development during embryogenesis.