A role for endogenous and radiation-induced DNA double-strand breaks in p53-dependent apoptosis during cortical neurogenesis

Hongzhe Li, Ninning Liu, Grace K. Rajendran, Thomas J Gernon, Jason K. Rockhill, Jeffrey L. Schwartz, Yansong Gu

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)513-522
Number of pages10
JournalRadiation Research
Volume169
Issue number5
DOIs
StatePublished - May 2008
Externally publishedYes

Fingerprint

neurogenesis
Double-Stranded DNA Breaks
Neurogenesis
apoptosis
strands
Microcephaly
deoxyribonucleic acid
Radiation
Apoptosis
cerebral cortex
p53 Genes
DNA
radiation
Intellectual Disability
Cerebral Cortex
embryos
radiation dosage
mutations
DNA End-Joining Repair
Embryonic Structures

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Radiology Nuclear Medicine and imaging
  • Biophysics
  • Radiation

Cite this

A role for endogenous and radiation-induced DNA double-strand breaks in p53-dependent apoptosis during cortical neurogenesis. / Li, Hongzhe; Liu, Ninning; Rajendran, Grace K.; Gernon, Thomas J; Rockhill, Jason K.; Schwartz, Jeffrey L.; Gu, Yansong.

In: Radiation Research, Vol. 169, No. 5, 05.2008, p. 513-522.

Research output: Contribution to journalArticle

Li, Hongzhe ; Liu, Ninning ; Rajendran, Grace K. ; Gernon, Thomas J ; Rockhill, Jason K. ; Schwartz, Jeffrey L. ; Gu, Yansong. / A role for endogenous and radiation-induced DNA double-strand breaks in p53-dependent apoptosis during cortical neurogenesis. In: Radiation Research. 2008 ; Vol. 169, No. 5. pp. 513-522.
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