RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Caspase-8 (Casp8) is critical for death receptor (DR)-induced apoptosis and also involved in nonapoptotic pathways. Disruption of Casp8 expression leads to embryonic lethality in mice between E10.5 and E11.5. RIP3 is responsible for the midgestational death of Casp8-deficient embryos. Casp8-deficient embryos with RIP3 also deleted (Casp8⁻/⁻Rip3⁻/⁻) are viable and mature into fertile adults with a full immune complement. These mice appear immunocompetent but develop lymphadenopathy by four months of age, marked by accumulation of abnormal T cells in the periphery, a phenotype reminiscent of mice with Fas-deficiency (lpr/lpr). Casp8 contributes to homeostatic control in the adult immune system; however, RIP3 and Casp8 are together completely dispensable for mammalian development. To determine whether Casp8 can hold RIP3 kinase-dependent death in check, the study used murine L929 cells, which require continued Casp8 expression for cell survival. Inhibition of Casp8 with siRNA or zVAD-fmk induced death, while treatment with RIP3-specific shRNA protected cells from death, indicating a RIP3-dependent necrotic death pathway. The MCMV M45 gene-encoded viral inhibitor of RIP activation (vIRA) blocks RIP3-dependent necrotic death. A tetra-alanine RHIM substitution mutant, M45mutRHIM, failed to suppress death induced by Casp8 siRNA or zVAD. Necrostatin-1 demonstrated that RIP1 kinase activity was necessary for necroptosis. The specific viral inhibitor of Casp8 activation (vICA) encoded by the MCMV M36 gene also induced this death pathway. Disruption of Casp8 expression leads to embryonic lethality in mice between E10.5 and E11.5, coincident with embryonic vascular, cardiac and hematopoietic defects. To evaluate the potential contribution of RIP3 to embryonic lethality, the study examined wild-type and Casp8⁻/⁻ embryos as well as extra-embryonic tissues for Rip3 expression. Rip3 transcript levels increased and tissue distribution broadened as embryonic development proceeded from E9.5 to E12.5 in both genotypes, indicating Rip3 transcript is not regulated by Casp8. Rip3 was prominent in the apical ectodermal ridge (AER) of the hind-limb bud and the tail bud, and expanded to include the fore-limb bud AER, midline of the spinal cord, branchial arches and intersomitic regions by E10.5 through E12.RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Caspase-8 (Casp8) is critical for death receptor (DR)-induced apoptosis and also involved in nonapoptotic pathways. Disruption of Casp8 expression leads to embryonic lethality in mice between E10.5 and E11.5. RIP3 is responsible for the midgestational death of Casp8-deficient embryos. Casp8-deficient embryos with RIP3 also deleted (Casp8⁻/⁻Rip3⁻/⁻) are viable and mature into fertile adults with a full immune complement. These mice appear immunocompetent but develop lymphadenopathy by four months of age, marked by accumulation of abnormal T cells in the periphery, a phenotype reminiscent of mice with Fas-deficiency (lpr/lpr). Casp8 contributes to homeostatic control in the adult immune system; however, RIP3 and Casp8 are together completely dispensable for mammalian development. To determine whether Casp8 can hold RIP3 kinase-dependent death in check, the study used murine L929 cells, which require continued Casp8 expression for cell survival. Inhibition of Casp8 with siRNA or zVAD-fmk induced death, while treatment with RIP3-specific shRNA protected cells from death, indicating a RIP3-dependent necrotic death pathway. The MCMV M45 gene-encoded viral inhibitor of RIP activation (vIRA) blocks RIP3-dependent necrotic death. A tetra-alanine RHIM substitution mutant, M45mutRHIM, failed to suppress death induced by Casp8 siRNA or zVAD. Necrostatin-1 demonstrated that RIP1 kinase activity was necessary for necroptosis. The specific viral inhibitor of Casp8 activation (vICA) encoded by the MCMV M36 gene also induced this death pathway. Disruption of Casp8 expression leads to embryonic lethality in mice between E10.5 and E11.5, coincident with embryonic vascular, cardiac and hematopoietic defects. To evaluate the potential contribution of RIP3 to embryonic lethality, the study examined wild-type and Casp8⁻/⁻ embryos as well as extra-embryonic tissues for Rip3 expression. Rip3 transcript levels increased and tissue distribution broadened as embryonic development proceeded from E9.5 to E12.5 in both genotypes, indicating Rip3 transcript is not regulated by Casp8. Rip3 was prominent in the apical ectodermal ridge (AER) of the hind-limb bud and the tail bud, and expanded to include the fore-limb bud AER, midline of the spinal cord, branchial arches and intersomitic regions by E10.5 through E12.