Mice with a homozygous gene trap vector insertion in mgcRacGAP die during pre-implantation development

In a phenotypic screen in mice using a gene trap approach in embryonic stem cells, we have identified a recessive loss-of-function mutation in the mgc RacGAP gene. Maternal protein is present in the oocyte. and mgcRacGAP gene transcription starts at the four-cell stage and persists throughout mouse p re-implantation development. Total mgcRacGAP deficiency results in pre-impl antation lethality. Such E3.5 embryos display a dramatic reduction in cell number, but undergo compaction and form a blastocoel. At E3.0-3.5, binuclea ted blastomeres in which the nuclei are partially interconnected are freque ntly observed, suggesting that mgcRacGAP is required for normal mitosis and cytokinesis in the pre-implantation embryo. All homozygous mutant blastocy sts fail to grow out on fibronectin-coated substrates, but a fraction of th em can still induce decidual swelling in vivo. The mgcRacGAP mRNA expressio n pattern in post-implantation embryos and adult mouse brain suggests a rol e in neuronal cells. Our results indicate that mgcRacGAP is essential for t he earliest stages of mouse embryogenesis, and add evidence that CYK-4-like proteins also play a role in microtubule-dependent steps in the cytokinesi s of vertebrate cells. In addition, the severe phenotype of null embryos in dicates that mgcRacGAP is functionally non-redundant and cannot be substitu ted by other GAPs during early cleavage of the mammalian embryo. (C) 2001 E lsevier Science ireland Ltd. All rights reserved.