Casp8 Knockout mouse models

As the apical death receptor caspase, mouse Casp8 is the ortholog of human CASP8 and carries tandem death effector domains that dock onto FADD within FAS, TRAIL receptor, or TNFR1 complex II, where dimerization and cleavage at Asp387 yield an active protease that processes BID and caspases 3 and 7. Equally important is its non-apoptotic role: caspase-8 cleaves RIPK1 and CYLD to restrain RIPK3 and MLKL dependent necroptosis, and it participates in FADD dependent inflammasome regulation. Germline deletion is embryonic lethal around E10.5 with yolk sac vascular failure, and that lethality is rescued by concurrent Ripk3 or Mlkl loss, the standard genetic proof that unrestrained necroptosis rather than lost apoptosis kills the embryo. Conditional flox alleles with epithelial or myeloid Cre are therefore mandatory for adult work, catalytically inactive C362A knockins isolate scaffolding, and human CASP8 knockins support study of patient variants causing lymphoproliferation and immunodeficiency.

Whole body loss of Casp8 gives the clearest readout when the question is whether the gene is required at all. Follow up tissue work can still move to a conditional allele if lethality or compensation appears.