DNA damage-induced neural precursor cell apoptosis requires p53 and caspase 9 but neither Bax nor caspase 3.
Programmed cell death (apoptosis) is critical for normal brain morphogenesis and may be triggered by neurotrophic factor deprivation or irreparable DNA damage. Members of the Bcl2 and caspase families regulate neuronal responsiveness to trophic factor withdrawal; however, their involvement in DNA damage-induced neuronal apoptosis is less clear. To define the molecular pathway regulating DNA damage-induced neural precursor cell apoptosis, we have examined the effects of drug and gamma-irradiation-induced DNA damage on telencephalic neural precursor cells derived from wild-type embryos and mice with targeted disruptions of apoptosis-associated genes. We found that DNA damage-induced neural precursor cell apoptosis, both in vitro and in vivo, was critically dependent on p53 and caspase 9, but neither Bax nor caspase 3 expression. Neural precursor cell apoptosis was also unaffected by targeted disruptions of Bclx and Bcl2, and unlike neurotrophic factor-deprivation-induced neuronal apoptosis, was not associated with a detectable loss of cytochrome c from mitochondria. The apoptotic pathway regulating DNA damage-induced neural precursor cell death is different from that required for normal brain morphogenesis, which involves both caspase 9 and caspase 3 but not p53, indicating that additional apoptotic stimuli regulate neural precursor cell numbers during telencephalic development.
D'Sa-Eipper
C
C
Department of Pathology, Division of Neuropathology, Washington University School of Medicine, St Louis, MO 63110, USA.
Leonard
J R
JR
Putcha
G
G
Zheng
T S
TS
Flavell
R A
RA
Rakic
P
P
Kuida
K
K
Roth
K A
KA
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D004249:DNA Damage; D018507:Gene Expression Regulation, Developmental; D016158:Genes, p53; D051379:Mice; D018345:Mice, Knockout; D009420:Nervous System / Q000196:embryology* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D015398:Signal Transduction / Q000235:genetics; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases