40
B. Conradt
various functions in programmed cell death have since been identified in
both vertebrates and invertebrates and are now collectively called
caspases (reviewed by Nicholson and Thornberry 1997; Cryns and Yuan
1998). Finally, a mammalian protein identified biochemically as required for programmed cell death in vitro, Apaf-l (Zhou et al. 1997),
shows similarity to the product of the ced-4 gene (Yuan and Horvitz
1992).
The importance of the mammalian counterparts of ced-9, ced-3, and
ced-4 in the programmed cell-death process has been confirmed by the
phenotypic analysis of mice carrying targeted mutations in the respective genes. Mice lacking functional copies of the bcl-2 or bcl-x gene,
which encode two Bcl-2-like cell-death inhibitors, exhibit developmental defects of varying degrees which can be attributed to increased
programmed cell death. While bcl-2- 1 - mice exhibit a defect in kidney
development, significantly lower numbers of a subset of cranial sensory
neurons at the time of birth, and increased loss of sensory, sympathetic,
and motor neurons postnatally (Veis et al. 1993; Michaelidis et al. 1996;
Pinon et al. 1997), Bcl-x deficient mice show signs of massive ectopic
cell death of immature hematopoietic cells and of neurons in the brain,
in the spinal cord and in the dorsal root ganglia, resulting in embryonic
lethality (Motoyama et al. 1995). Mice deficient in Caspases 3 or 9, or
in Apaf-l, in contrast, have defects indicative of a lack of programmed
cell death. In all three cases, brain development is severely affected due
to reduced levels of programmed cell death resulting in hyperplasia, in
disorganized brain development, and subsequently in abnormal skull
formation, resulting in lethality (Kuida et al. 1996; Woo et al. 1998;
Kuida et al. 1998; Hakem et al. 1998; Cecconi et al. 1998; Yoshida et al.
1998). Apaj-l-/- mice, in addition, exhibit defects in the sculpting of the
limbs and in the formation of the palate (Cecconi et al. 1998; Yoshida et
al. 1998), two processes known to require programmed cell death (Garcia-Martinez et al. 1993; Ferguson 1988; reviewed by Coucouvanis et al.
1995).
B. Conradt
various functions in programmed cell death have since been identified in
both vertebrates and invertebrates and are now collectively called
caspases (reviewed by Nicholson and Thornberry 1997; Cryns and Yuan
1998). Finally, a mammalian protein identified biochemically as required for programmed cell death in vitro, Apaf-l (Zhou et al. 1997),
shows similarity to the product of the ced-4 gene (Yuan and Horvitz
1992).
The importance of the mammalian counterparts of ced-9, ced-3, and
ced-4 in the programmed cell-death process has been confirmed by the
phenotypic analysis of mice carrying targeted mutations in the respective genes. Mice lacking functional copies of the bcl-2 or bcl-x gene,
which encode two Bcl-2-like cell-death inhibitors, exhibit developmental defects of varying degrees which can be attributed to increased
programmed cell death. While bcl-2- 1 - mice exhibit a defect in kidney
development, significantly lower numbers of a subset of cranial sensory
neurons at the time of birth, and increased loss of sensory, sympathetic,
and motor neurons postnatally (Veis et al. 1993; Michaelidis et al. 1996;
Pinon et al. 1997), Bcl-x deficient mice show signs of massive ectopic
cell death of immature hematopoietic cells and of neurons in the brain,
in the spinal cord and in the dorsal root ganglia, resulting in embryonic
lethality (Motoyama et al. 1995). Mice deficient in Caspases 3 or 9, or
in Apaf-l, in contrast, have defects indicative of a lack of programmed
cell death. In all three cases, brain development is severely affected due
to reduced levels of programmed cell death resulting in hyperplasia, in
disorganized brain development, and subsequently in abnormal skull
formation, resulting in lethality (Kuida et al. 1996; Woo et al. 1998;
Kuida et al. 1998; Hakem et al. 1998; Cecconi et al. 1998; Yoshida et al.
1998). Apaj-l-/- mice, in addition, exhibit defects in the sculpting of the
limbs and in the formation of the palate (Cecconi et al. 1998; Yoshida et
al. 1998), two processes known to require programmed cell death (Garcia-Martinez et al. 1993; Ferguson 1988; reviewed by Coucouvanis et al.
1995).