Bcl-X-L-Caspase-9 interactions in the developing nervous system: Evidence for multiple death pathways

Citation
Au. Zaidi et al., Bcl-X-L-Caspase-9 interactions in the developing nervous system: Evidence for multiple death pathways, J NEUROSC, 21(1), 2001, pp. 169-175
Citations number
34
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Neurosciences & Behavoir
Journal title
JOURNAL OF NEUROSCIENCE
ISSN journal
0270-6474 → ACNP
Volume
21
Issue
1
Year of publication
2001
Pages
169 - 175
Database
ISI
SICI code
0270-6474(20010101)21:1<169:BIITDN>2.0.ZU;2-2
Abstract
Programmed cell death is critical for normal nervous system development and is regulated by Bcl-2 and Caspase family members. Targeted disruption of b cl-x(L), an antiapoptotic bcl-2 gene family member, causes massive death of immature neurons in the developing nervous system whereas disruption of ca spase-9, a proapoptotic caspase gene family member, leads to decreased neur onal apoptosis and neurodevelopmental abnormalities. To determine whether B cl-X-L and Caspase-9 interact in an obligate pathway of neuronal apoptosis, bcl-x/caspase-9 double homozygous mutants were generated. The increased ap optosis of immature neurons observed in Bcl-X-L-eficient embryos was comple tely prevented by concomitant Caspase-9 deficiency. In contrast, bcl-x(-/-) /caspase-9(-/-) embryonic mice exhibited an expanded ventricular zone and n euronal malformations identical to that observed in mice lacking only Caspa se-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 telence phalic neurons, we compared the effects of cytosine arabinoside (AraC), a k nown neuronal apoptosis inducer, on wild-type, Bcl-X-L-, Bax-, Caspase-9-, Caspase-3-, and p53-deficient telencephalic neurons in vitro. AraC caused e xtensive apoptosis of wild-type and Bcl-X-L-deficient neurons. p53- and Bax - deficient neurons showed marked protection from AraC-induced death, where as Caspase-9- and Caspase-3-deficient neurons showed minimal or no protecti on, respectively. These findings contrast with our previous investigation o f AraC-induced apoptosis of telencephalic neural precursor cells in which d eath was completely blocked by p53 or Caspase-9 deficiency but not Bax defi ciency. In total, these results indicate a transition from Caspase-9- to Ba x- and Bcl-X-L-mediated neuronal apoptosis.