Gene targeting in the analysis of mammalian apoptosis and TNF receptor superfamily signaling

Apoptosis, or programed cell death (PCD), is the subject of much current investigative interest. Developing embryos and many adult organ systems require the tight coupling of cellular proliferation and PCD to ensure proper organogenesis and optimal tissue function. Over the past decade, our knowledge 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 plethora of novel signaling proteins, including molecules that are directly involved in apoptosis signaling, and others that regulate the induction of cell death. This two-part review focuses on the biology of apoptosis and signaling through members of the TNF receptor superfamily as revealed by the study of gene-targeted "knockout" mice. These genetic mutant animals are invaluable tools not only for confirming or refuting a proposed function of a particular gene in an in vivo setting. but also for uncovering novel functions for a gene that were not anticipated from conventional in vitro experiments. In the field of apoptosis, as for many other areas of biomedical research, knockout mice and cell lines can be used as models for studying human disease, with the ultimate goal of developing therapeutic strategies.