A role for endogenous and radiation-induced DNA double-strand breaks in p53-dependent apoptosis during cortical neurogenesis.
Prenatal exposure to low-dose radiation increases the risk of microcephaly and/or mental retardation. Microcephaly is also associated with genetic mutations that affect the non-homologous end-joining pathway of DNA double-strand break repair. To examine the link between these two causal factors, we characterized the neural developmental effects of acute radiation exposure in mouse littermate embryos harboring mutations in the Ku70 and p53 genes. Both low-dose radiation exposure and Ku70 deficiency induced morphologically indistinguishable cortical neuronal apoptosis. Irradiated Ku70-deficient embryos displayed anatomical damage indicative of increased radiosensitivity in the developing cerebral cortex. Deleting the p53 gene not only rescued cortical neuronal apoptosis at all levels but also restored the in vitro growth of Ku70-deficient embryonic fibroblasts despite the presence of unrepaired DNA/chromosomal breaks. The results confirm the role of DNA double-strand breaks as a common causative agent of apoptosis in the developing cerebral cortex. Furthermore, the findings suggest a disease mechanism by which the presence of endogenous DNA double-strand breaks in the newly generated cortical neurons becomes radiomimetic when DNA end joining is defective. This in turn activates p53-dependent neuronal apoptosis and leads to microcephaly and mental retardation.
Li
Hongzhe
H
Department of Radiation Oncology, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Liu
Ninning
N
Rajendran
Grace K
GK
Gernon
Thomas J
TJ
Rockhill
Jason K
JK
Schwartz
Jeffrey L
JL
Gu
Yansong
Y
D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000528:radiation effects*; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology / Q000378:metabolism* / Q000528:radiation effects*; D002875:Chromosomes / Q000235:genetics; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D000072200:Ku Autoantigen; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen