PROVIRUS INTEGRATION INTO A GENE ENCODING A UBIQUITIN-CONJUGATING ENZYME RESULTS IN A PLACENTAL DEFECT AND EMBRYONIC LETHALITY

Ubiquitin-conjugating enzymes (E2 or Ubc) constitute a family of conse rved proteins that play a key role in ubiquitin-dependent degradation of proteins in eukaryotes, me describe here a transgenic mouse strain, where retrovirus integration into an Ubc gene, designated UbcM4, resul ts in a recessive-lethal mutation, UbcM4 is the mouse homologue of the previously described human UbcH7 that is involved in the in vitro ubi quitination of several proteins including the tumor suppressor protein p53. The provirus is located in the first intron of the gene, When bo th alleles are mutated the level of steady-state mRNA is reduced by ab out 70%. About a third of homozygous mutant embryos die around day 11. 5 of gestation. Embryos that survive that stage are growth retarded an d die perinatally, The lethal phenotype is most likely caused by impai rment of placenta development as this is the only organ that consisten tly shelved pathological defects, The placental labyrinth is drastical ly reduced in size and vascularization is disturbed. The UbcM4 mouse m utant represents the first example in mammals of a mutation in a gene involved in ubiquitin conjugation, Its recessive-lethal phenotype demo nstrates that the ubiquitin system plays an essential role during mous e development.