Defective embryonic neurogenesis in Ku-deficient but not DNA-dependent protein kinase catalytic subunit-deficient mice

Mammalian nonhomologous DNA end joining employs Ku70, Ku80. DNA-dependent p rotein kinase catalytic subunit (DNA-PKcs), XRCC4 and DNA ligase IV (Lig4). Herein, we show that Ku70 and Ku80 deficiency but not DNA-PKcs deficiency results in dramatically increased death of developing embryonic neurons in mice. The Ku-deficient phenotype is qualitatively similar to, but less seve re than, that associated with XRCC4 and Lig4 deficiency. The lack of a neur onal death phenotype in DNA-PKcs-deficient embryos and the milder phenotype of Ku-deficient versus XRCC4- or Lig4-deficient embryos correlate with rel ative leakiness of residual end joining in these mutant backgrounds as assa yed by a V(D)J recombination end joining assay. We conclude that normal dev elopment of the nervous system depends on the four evolutionarily conserved nonhomologous DNA end joining factors.