TARGETED DISRUPTION OF THE MOUSE CASPASE-8 GENE ABLATES CELL-DEATH INDUCTION BY THE TNF RECEPTORS, FAS APO1, AND DR3 AND IS LETHAL PRENATALLY/

Homozygous targeted disruption of the mouse Caspase 8 (Casp8) gene was found to be lethal in utero. The Caspase 8 null embryos exhibited imp aired heart muscle development and congested accumulation of erythrocy tes. Recovery of hematopoietic colony-forming cells from the embryos w as very low. In fibroblast strains derived from these embryos, the TNF receptors, Fas/Apo1, and DR3 were able to activate the Jun N-terminal kinase and to trigger I kappa B alpha phosphorylation and degradation . They failed, however, to induce cell death, while doing so effective ly in wild-type fibroblasts. These findings indicate that Caspase 8 pl ays a necessary and nonredundant role in death induction by several re ceptors of the TNF/NGF family and serves a vital role in embryonal dev elopment.