Partial rescue of Brca1 (5-6) early embryonic lethality by p53 or p21 null mutation.

Mutations in the mouse Brca1 gene cause lethality at different embryonic stages. We have shown that Brca1 mutant embryos, in which the fifth and sixth exons of Brca1 are deleted die before E7.5 and show decreased cellular proliferation. Brca1 mutants also show decreased expression of mdm2, a gene encoding an inhibitor of p53 activity. Thus, we have proposed that the reduction in mdm2 expression in Brca1 (5-6) mutants might lead to increased p53 activity. Consistent with this finding, the expression of p21, which encodes a G1 cell cycle inhibitor and is a target for p53 transcriptional activation was dramatically increased in the Brca1 (5-6) mutants, suggesting that impaired cellular proliferation could be due to a G1 cell-cycle arrest, caused by increased p21 levels. To test this hypothesis, we generated mice double mutant for Brca1 (5-6) and p53, or Brca1 (5-6) and p21. Mutation in either p53 or p21 prolonged the survival of Brca1 (5-6) mutant embryos from E7.5 to E9.5. The development of most Brca1 (5-6): p21 double-mutant embryos was comparable to that of their wild-type littermates, although no mutant survived past E10.5. The fact that mutation of neither p53 nor p21 completely rescued Brca1 (5-6) embryos suggests that their lethality is likely due to a multi-factorial process.