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 protein 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 severe than, that associated with XRCC4 and Lig4 deficiency. The lack of a neuronal death phenotype in DNA-PKcs-deficient embryos and the milder phenotype of Ku-deficient versus XRCC4- or Lig4-deficient embryos correlate with relative leakiness of residual end joining in these mutant backgrounds as assayed by a V(D)J recombination end joining assay. We conclude that normal development of the nervous system depends on the four evolutionarily conserved nonhomologous DNA end joining factors.
Gu
Y
Y
Howard Hughes Medical Institute, The Children's Hospital, and Center for Blood Research, and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Sekiguchi
J
J
Gao
Y
Y
Dikkes
P
P
Frank
K
K
Ferguson
D
D
Hasty
P
P
Chun
J
J
Alt
F W
FW
D000818:Animals; D034961:Antigens, Nuclear; D017209:Apoptosis; D002478:Cells, Cultured; D002490:Central Nervous System / Q000002:abnormalities / Q000196:embryology* / Q000201:enzymology; D002540:Cerebral Cortex / Q000166:cytology / Q000473:pathology; D004265:DNA Helicases; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000502:physiology; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000502:physiology*; D004027:Diencephalon / Q000166:cytology / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D000072200:Ku Autoantigen; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000166:cytology / Q000473:pathology; D009687:Nuclear Proteins / Q000502:physiology*; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011995:Recombination, Genetic; D013116:Spinal Cord / Q000166:cytology / Q000473:pathology; D013997:Time Factors
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; C000607893:LIG4 protein, human; D009687:Nuclear Proteins; C101467:XRCC4 protein, human; D051747:DNA-Activated Protein Kinase; D017346:Protein Serine-Threonine Kinases; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen; D011088:DNA Ligases; D000072481:DNA Ligase ATP