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
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.