1998; O’Reilly et al., 2002). Furthermore, DRG neurons from these mice undergo
factor-withdrawal-induced cell death as wild-type mice (O’Reilly et al., 2002). These
results suggest that caspase-2 is not essential for normally occurring cell death, or
plays a redundant role in apoptosis. Some support for a compensatory pathway in
casp2-deficient cells comes from a recent report where the authors found that in casp2-
null neurons, the NGF-deprivation-induced, caspase-2-dependent cell death
becomes dependent on the caspase-9 pathway, and that casp2-/- neurons show a
threefold compensatory elevation of caspase-9 expression (Troy et al., 2001).
Caspase-12 is unique in that it localizes primarily to the endoplasmic reticulum
(ER) (Nakagawa et al., 2000). Caspase-12 is activated by ER stress, such as
accumulation of excess proteins in ER, and in response to the disruption of ER
calcium homeostasis, but not by TNFR or mitochrondrially mediated death signals
(Nakagawa et al., 2000). Casp12-null mice are resistant to ER stress-induced
apoptosis, but their cells undergo apoptosis in response to other death stimuli.
Interestingly, caspase-12-deficient cortical neurons are defective in apoptosis induced
by amyloid-beta protein, but not by staurosporine or trophic factor deprivation
(Nakagawa et al., 2000). Thus, caspase-12 appears to be specifically involved in certain
stress response pathways, independently of the TNFR and mitochondrial pathways
of apoptosis.
Unpublished data on casp6 k/o suggest that ablation of this caspase has no
deleterious effect in mice, whereas casp7 mutants are embryonically lethal (cited in
Zheng et al., 1999).
8.2
Knockout of the caspase adaptorsIn C. elegans, loss-of-function mutants of ced-4 show complete abrogation of
developmentally programmed cell death (Yuan and Horvitz, 1990). In Drosophila,
the hypomorphic alleles of dark, the APAF-1 homolog, attenuate programmed cell
deaths during development, causing hyperplasia of the central nervous system, ectopic
melanotic tumors, and defective wings (Kanuka et al., 1999; Rodriguiez et al., 1999;
Zhou et al., 1999). Furthermore, in dark mutants, caspase activation is suppressed,
and killing by RPR, GRIM, and HID, is substantially suppressed (Kanuka et al.,
1999; Rodriguez et al., 1999). In the mouse, the apaf-1-null mutation is
embryonically or perinatally lethal (Cecconi et al., 1998; Yoshida et al., 1998b). The
apaf-1-deficient embryos show a range of craniofacial abnormalities resulting from
aberrant midline fusion of craniofacial structures, and brain abnormalities including
ectopic forebrain cell masses, similar to those seen in casp3 and casp9 mutant animals.
In E12.5, the retina of apaf1-/- mutants is thicker than normal and occupies the optic
cup, and the lenses are smaller and incorrectly polarized. Delayed removal of
interdigital webbing in apaf1-/- embryos is also seen (Cecconi et al., 1998; Yoshida et
al., 1998b). Caspase-3 activation is reduced in apaf1-deficient cells, and mutant cells
show resistance to a variety of apoptosis stimuli (Cecconi et al., 1998; Yoshida et al.,
1998b). These data indicate that the Apaf-1 pathway plays a nonredundant role in
THE ROLE OF CASPASES IN APOPTOSIS 47