Partial rescue of Brca15–6 early embryonic lethality by p53 or p21 null mutation

Abstract

Mutations in the mouse Brca1 gene cause lethality at different embryonic stages^1–3. We have shown that Brca1^5–6 mutant embryos, in which the fifth and sixth exons of Brcal are deleted, die before E7.5 and show decreased cellular proliferation². Brca1^5–6 mutants also show decreased expression of mdm2, a gene encoding an inhibitor ofp53 activity⁴. 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^5–10 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.