Apoptosis, or programed cell death (PCD), is the subject of much current in
vestigative interest. Developing embryos and many adult organ systems requi
re the tight coupling of cellular proliferation and PCD to ensure proper or
ganogenesis and optimal tissue function. Over the past decade, our knowledg
e of the genetic basis underlying the execution of apoptosis in mammals has
progressed enormously, thanks largely to groundbreaking studies performed
in the nematode Caenorhabditis elegans. In contrast, the components of the
signaling apparatus that links the various death stimuli and the receptors
they stimulate to the execution mechanism remain relatively unknown. It is
only in the past 4 years that studies of signal transduction via members of
the tumor necrosis factor (TNF) receptor superfamily have identified a ple
thora of novel signaling proteins, including molecules that are directly in
volved in apoptosis signaling, and others that regulate the induction of ce
ll death. This two-part review focuses on the biology of apoptosis and sign
aling through members of the TNF receptor superfamily as revealed by the st
udy of gene-targeted "knockout" mice. These genetic mutant animals are inva
luable tools not only for confirming or refuting a proposed function of a p
articular gene in an in vivo setting. but also for uncovering novel functio
ns for a gene that were not anticipated from conventional in vitro experime
nts. In the field of apoptosis, as for many other areas of biomedical resea
rch, knockout mice and cell lines can be used as models for studying human
disease, with the ultimate goal of developing therapeutic strategies.