Two morsels of wisdom that I have acquired are: first, the study of spontaneously arisen mutant mice that have spectacular phenotypes will inevitably lead to remarkable insights; and second, outstanding scientific advances often result from the serendipitous convergence of previously independent lines of research. The paper that was published in 1992 by Watanabe-Fukunaga et al. exemplifies both of these points.

For a long time immunologists had been fascinated by the progressive lymphadenopathy and systemic autoimmune disease that the lpr and lprcg (allelic) mutant mouse strains develop. Meanwhile, the groups of Krammer (Trauth et al.) and Yonehara (Yonehara et al.) had unintentionally generated monoclonal antibodies that induced apoptotic cell death in certain human tumour-derived cell lines. The cloning of the Fas gene by Itoh et al. showed that FAS (also known as CD95, APO1 and TNFRSF6) is related to tumour necrosis factor receptor 1 (TNFR1) and (similarly to TNFR1) can trigger apoptosis when stimulated.

whenever scientists hypothesized that a process involved FAS-mediated apoptosis, they could use lpr mice to check this

The physiological function of FAS was revealed by Watanabe-Fukunaga et al., who showed that the lpr mice have an insertion in the 5′ region of the Fas gene that markedly decreases expression of Fas mRNA, and that lprcg mice have a point mutation that affects the 'death domain' in the intracellular region of FAS. This residue is highly conserved among 'death receptors' (such as TNFR1). Elegant biochemical studies showed that the lprcg point mutation impairs FAS-mediated apoptosis signalling. Subsequent work showed that this residue is crucial for the interaction of FAS with the adaptor protein FAS-associated death domain protein (FADD; also known as MORT1), which in turn facilitates the recruitment and activation of caspase 8 to unleash cell demolition. An important practical outcome of the study by Watanabe-Fukunaga et al. was that whenever scientists hypothesized that a process involved FAS-mediated apoptosis, they could use lpr mice to check this.

Within a few years of the paper by Watanabe-Fukunaga et al., translational studies had shown that mutations in the FAS gene are the cause of autoimmune lymphoproliferative syndrome (ALPS) in children, which closely resembles the immune system abnormalities in lpr mice. Curiously, these inherited mutations function in a dominant manner, but the parent who carries the mutation is usually healthy, which indicates that a polymorphism in an additional gene might contribute to pathogenesis. Thus, many interesting questions in this area of research remain to be answered.