Xrcc2 is required for genetic stability, embryonic neurogenesis and viability in mice

Repair of DNA damage by homologous recombination has only recently been est ablished as an important mechanism in maintaining genetic stability in mamm alian cells. The recently cloned Xrcc2 gene is a member of the mammalian Ra d51 gene family, thought to be central to homologous recombination repair. To understand its function in mammals, we have disrupted Xrcc2 in mice. No Xrcc2(-/-) animals were found alive, with embryonic lethality occurring fro m midgestation. Xrcc2(-/-) embryos surviving until later stages of embryoge nesis commonly showed developmental abnormalities and died at birth. Neonat al lethality, apparently due to respiratory failure, was associated with a high frequency of apoptotic death of postmitotic neurons in the developing brain, leading to abnormal cortical structure. Embryonic cells showed genet ic instability, revealed by a high level of chromosomal aberrations, and we re sensitive to gamma -rays. Our findings demonstrate that homologous recom bination has an important role in endogenous damage repair in the developin g embryo. Xrcc2 disruption identifies a range of defects that arise from ma lfunction of this repair pathway, and establishes a previously unidentified role for homologous recombination repair in correct neuronal development.