Oxidative damage and defective DNA repair is linked to apoptosis of migrating neurons and progenitors during cerebral cortex development in Ku70-deficient mice.
DNA repair plays a critical, but imprecisely defined role in neuronal survival during cortical neurogenesis. We examined cortical development in mice deficient for the DNA end-joining protein, Ku70. At gestational day 14.5, corresponding to the peak of neurogenesis, the Ku70(-/-) embryonic cerebral cortex displayed 25- to 30-fold more cell death than heterozygous littermates, as judged by DNA breaks, pyknosis and active caspase-3. In Ku70(-/-) embryos only, large clusters of dying neurons were found in the intermediate zone. Cell death declined until P4, when the number of dying cells became comparable to that in heterozygous mice. Two groups of dying cells were evident: a GLAST(+) neural progenitor population in the subventricular and ventricular zones, and a doublecortin(+) immature neuron population in the intermediate zone, the latter exhibiting strong staining for oxidative DNA damage. Antioxidants and lower oxygen tension reduced the high levels of neuronal death in primary cortical cultures derived from Ku70(-/-) mice, but not the low levels of cell death in wildtype cortical cultures. Results indicate migrating cortical neurons undergo oxidative DNA damage, which is normally repaired by non-homologous end joining. Failure to repair oxidative damage triggers a form of apoptosis involving caspase-3 activation.
Narasimhaiah
Roopashree
R
Program in Neuroscience and Behavior, Department of Biology, Wesleyan University, Middletown, CT 06459-0171, USA.
Tuchman
Alexander
A
Lin
Stanley L
SL
Naegele
Janice R
JR
D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics*; D017209:Apoptosis / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D000072200:Ku Autoantigen; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D011247:Pregnancy; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen