Genetics of Apoptosis

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controlling cell number during brain and eye development and the morphogenetic
cell death in the brain, skull, face, eye, and limbs. Additional defects seen in apaf1-/-
mutants not seen in casp9-/- mutants indicate that Apaf-1 has roles in developmental
cell death that are not dependent on caspase-9 activity and suggest that Apaf-1 may
mediate the activation of other caspases.
The fadd k/o in mice is embryonically lethal by day 12.5 (Zhang, J. et al., 1998;
Yeh et al., 1998). fadd-/- embryos show a delayed and underdeveloped phenotype,
somewhat similar to the casp8 k/o phenotype. At E10.5, the ventricular myocardium
is thinner than normal, and the inner trabeculation is poorly developed, indicating
that FADD plays a nonredundant role in heart development. The mutants also show
abdominal hemorrhage that is not caused by abnormal blood-vessel development.
fadd-/- MEFs are resistant to apoptosis induced by CD95, TNFR-1, or DR3, but not
DR4; however, apoptosis induced by overexpression of oncogenes or by cytotoxic
drugs is not impaired in these cells. FADD also appears to be required for T-cell
proliferation. The similarity in the phenotypes of casp8 and fadd mutant mice suggests
that FADD and caspase-8 are essential for apoptosis mediated by many of the TNFRs,
but dispensable for death pathways induced by other stimuli.
The caspase mutant and k/o data suggest that while some caspases play essential
roles in specific cell-death pathways, others are either redundant or compensated for
in the k/o situations. Nevertheless, the results show that individual caspases may
participate in apoptosis execution in a cell—and signal-specific manner.


48 GENETICS OF APOPTOSIS

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