THE VAV PROTOONCOGENE IS REQUIRED EARLY IN EMBRYOGENESIS BUT NOT FOR HEMATOPOIETIC DEVELOPMENT IN-VITRO

Previous studies have suggested that the vav proto-oncogene plays an i mportant role in hematopoiesis. To study this further, we have ablated the vav protooncogene by homologous recombination in embryonic stem ( ES) cells. Homozygous vav (-/-) ES clones differentiate normally in cu lture and generate cells of erythroid, myeloid and mast cell lineages. Mice heterozygous for the targeted vav allele do not display any obvi ous abnormalities. However, homozygous embryos die very early during d evelopment. Crosses of vav (+/-) heterozygous mice yield apparently no rmal vav (-/-) E3.5 embryos but not post-implantation embryos (greater than or equal to E7.5). Furthermore, homozygous vav (-/-) blastocysts do not hatch in vitro. These results indicate that vav is essential f or an early developmental step(s) that precedes the onset of hematopoi esis. Consistent with the phenotypic analysis of vav (-/-) embryos, we have identified Vav immunoreactivity in the extra-embryonic trophobla stic cell layer but not in the inner embryonic cell mass of E3.5 preim plantation embryos or in the egg cylinder of E6.5 and E7.5 postimplant ation embryos. These results suggest that the vav gene is essential fo r normal trophoblast development and for implantation of the developin g embryo.