PMID:11150333

Citation	Zaidi, AU, D'Sa-Eipper, C, Brenner, J, Kuida, K, Zheng, TS, Flavell, RA, Rakic, P and Roth, KA (2001) Bcl-X(L)-caspase-9 interactions in the developing nervous system: evidence for multiple death pathways. J. Neurosci. 21:169-75
Abstract	Programmed cell death is critical for normal nervous system development and is regulated by Bcl-2 and Caspase family members. Targeted disruption of bcl-x(L), an antiapoptotic bcl-2 gene family member, causes massive death of immature neurons in the developing nervous system whereas disruption of caspase-9, a proapoptotic caspase gene family member, leads to decreased neuronal apoptosis and neurodevelopmental abnormalities. To determine whether Bcl-X(L) and Caspase-9 interact in an obligate pathway of neuronal apoptosis, bcl-x/caspase-9 double homozygous mutants were generated. The increased apoptosis of immature neurons observed in Bcl-X(L)-deficient embryos was completely prevented by concomitant Caspase-9 deficiency. In contrast, bcl-x(-/-)/caspase-9(-/-) embryonic mice exhibited an expanded ventricular zone and neuronal malformations identical to that observed in mice lacking only Caspase-9. These results indicate both epistatic and independent actions of Bcl-X(L) and Caspase-9 in neuronal programmed cell death. To examine Bcl-2 and Caspase family-dependent apoptotic pathways in telencephalic neurons, we compared the effects of cytosine arabinoside (AraC), a known neuronal apoptosis inducer, on wild-type, Bcl-X(L)-, Bax-, Caspase-9-, Caspase-3-, and p53-deficient telencephalic neurons in vitro. AraC caused extensive apoptosis of wild-type and Bcl-X(L)-deficient neurons. p53- and Bax-deficient neurons showed marked protection from AraC-induced death, whereas Caspase-9- and Caspase-3-deficient neurons showed minimal or no protection, respectively. These findings contrast with our previous investigation of AraC-induced apoptosis of telencephalic neural precursor cells in which death was completely blocked by p53 or Caspase-9 deficiency but not Bax deficiency. In total, these results indicate a transition from Caspase-9- to Bax- and Bcl-X(L)-mediated neuronal apoptosis.
Links	PubMed
Keywords	Animals; Apoptosis/physiology; Caspase 3; Caspase 9; Caspases/deficiency; Caspases/genetics; Caspases/metabolism; Cells, Cultured; Cytarabine/pharmacology; Ganglia, Spinal/embryology; Ganglia, Spinal/pathology; Genes, Lethal; Heterozygote; Homozygote; Immunohistochemistry; In Situ Nick-End Labeling; Liver/embryology; Liver/pathology; Mice; Mice, Knockout; Nervous System/cytology; Nervous System/drug effects; Nervous System/embryology; Nervous System/metabolism; Neurons/cytology; Neurons/drug effects; Neurons/metabolism; Proto-Oncogene Proteins/deficiency; Proto-Oncogene Proteins/genetics; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins c-bcl-2/deficiency; Proto-Oncogene Proteins c-bcl-2/genetics; Proto-Oncogene Proteins c-bcl-2/metabolism; Telencephalon/cytology; Telencephalon/drug effects; Telencephalon/embryology; Telencephalon/metabolism; Tumor Suppressor Protein p53/deficiency; Tumor Suppressor Protein p53/genetics; Tumor Suppressor Protein p53/metabolism; bcl-2-Associated X Protein; bcl-X Protein
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