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¹ Department of Animal Development and Physiology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8507, Japan
² Department of Developmental Biology, National Institute for Basic Biology, Okazaki 444-8585, Japan
³ Division of Embryology and Genetics, Laboratory for Amphibian Biology, Faculty of Science, Hiroshima University, Higashihiroshima 739-8526, Japan
⁴ Department of Zoology, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan
⁵ Department of Science for Laboratory Animal Experimentation, Research Institute for Microbial Diseases, Osaka University, Suita 565-0871, Japan

FADD is an adaptor protein that transmits apoptotic signals from death receptors such as Fas to downstream initiator caspases in mammals. We have identified and characterized the Xenopus orthologue of mammalian FADD (xFADD). xFADD contains both a death effector domain (DED) and a death domain (DD) that are structurally homologous to those of mammalian FADD. We observed xFADD binding to Xenopus caspase-8 and caspase-10 as well as to human caspase-8 and Fas through interactions with their homophilic DED and DD domains. When over-expressed, xFADD was also able to induce apoptosis in wild-type mouse embryonic fibroblasts (MEF), but not in caspase-8-deficient MEF cells. In contrast, DED-deficient xFADD (xFADDdn) acted as a dominant-negative mutant and prevented Fas-mediated apoptosis in mammalian cell lines. These results indicate that xFADD transmits apoptotic signals from Fas to caspase-8. Furthermore, we found that transgenic animals expressing xFADD in the developing heart or eye under the control of tissue-specific promoters show abnormal phenotypes. Taken together, these results suggest that xFADD can substitute functionally for its mammalian homologue in death receptor-mediated apoptosis, and we suggest that xFADD functions as a pro-apoptotic adaptor molecule in frogs. Thus, the structural and functional similarities between xFADD and mammalian FADD provide evidence that the apoptotic pathways are evolutionally conserved across vertebrate species.

^* Correspondence: E-mail: ksakamak{at}virus.kyoto-u.ac.jp

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