LIGAND-DEPENDENT DEVELOPMENT OF THE ENDOTHELIAL AND HEMATOPOIETIC LINEAGES FROM EMBRYONIC MESODERMAL CELLS EXPRESSING VASCULAR ENDOTHELIAL GROWTH-FACTOR RECEPTOR-2

The existence of a common precursor for endothelial and hemopoietic ce lls, termed the hemangioblast, has been postulated since the beginning of the century, Recently, deletion of the endothelial-specific vascul ar endo thelial growth factor receptor 2 (VEGFR2) by gene targeting ha s shown that both endothelial and hemopoietic cells are absent in homo zygous null mite, This observation suggested that VEGFR2 could be expr essed by the hemangioblast and essential for its further differentiati on along both lineages, However, it was not possible to exclude the hy pothesis that hemopoietic failure was a secondary effect resulting fro m the absence of an endothelial cell microenvironment. To distinguish between these two hypotheses, we have produced a mAb directed against the extracellular domain of avian VEGFR2 and isolated VEGFR2+ cells fr om the mesoderm of chicken embryos at the gastrulation stage, We have found that in clonal cultures, a VEGPR2+ cell gives rise to either a h emopoietic or an endothelial cell colony. The developmental decision a ppears to be regulated by the binding of two different VEGFR2 ligands, Thus, endothelial differentiation requires VEGF, whereas hemopoietic differentiation occurs in the absence of VEGF and is significantly red uced by soluble VEGFR2, showing that this process could be mediated by a second, yet unidentified, VEGFR2 ligand, These observations thus su ggest strongly that in the absence of the VEGFR2 gene product, the pre cursors of both hemopoietic and vascular endothelial lineages cannot s urvive. These cells therefore might be the initial targets of the VEGF R2 null mutation.