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 morphogenesi s and may be triggered by neurotrophic factor deprivation or irreparable DN A damage. Members of the Bcl2 and caspase families regulate neuronal respon siveness to trophic factor withdrawal; however, their involvement in DNA da mage-induced neuronal apoptosis is less clear. To define the molecular path way regulating DNA damage-induced neural precursor cell apoptosis, we have examined the effects of drug and gamma -irradiation-induced DNA damage on t elencephalic 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 Pax nor caspase 3 expression. Neural precursor cell apoptosis was also unaffected by targe ted disruptions of Bclx and Bcl2, and unlike neurotrophic factor-deprivatio n-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 no rmal brain morphogenesis, which involves both caspase 9 and caspase 3 but n ot p53, indicating that additional apoptotic stimuli regulate neural precur sor cell numbers during telencephalic development.