title: Bcl-X(L)-caspase-9 interactions in the developing nervous system: evidence for multiple death pathways.
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.
authors.affiliation: Department of Pathology and Immunology, Division of Neuropathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: A U
authors.initials: AU
authors.lastname: Zaidi
authors.forename: C
authors.initials: C
authors.lastname: D'Sa-Eipper
authors.forename: J
authors.initials: J
authors.lastname: Brenner
authors.forename: K
authors.initials: K
authors.lastname: Kuida
authors.forename: T S
authors.initials: TS
authors.lastname: Zheng
authors.forename: R A
authors.initials: RA
authors.lastname: Flavell
authors.forename: P
authors.initials: P
authors.lastname: Rakic
authors.forename: K A
authors.initials: KA
authors.lastname: Roth
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003561:Cytarabine / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000196:embryology / Q000473:pathology; D005804:Genes, Lethal; D006579:Heterozygote; D006720:Homozygote; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000196:embryology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009420:Nervous System / Q000166:cytology / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013687:Telencephalon / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
chemical_list: C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D003561:Cytarabine; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases