NDLI: RIP3 mediates the embryonic lethality of caspase-8-deficient mice

Content Provider	PubMed Central
Author	Kaiser, William J. Upton, Jason W. Long, Alyssa B. Devon, Livingston-rosanoff Daley, Lisa P. Hakem, Razqallah Caspary, Tamara Mocarski, Edward S.
Abstract	Apoptosis and necroptosis are complementary pathways controlled by common signaling adaptors, kinases and proteases; among these, caspase-8 (Casp8) is critical for death receptor (DR)-induced apoptosis. This caspase has also been implicated in nonapoptotic pathways that regulate Fas-associated via death domain (FADD)-dependent signaling and other less defined biological processes as diverse as innate immune signaling and myeloid or lymphoid differentiation patterns 1. Casp8 suppresses RIP3/RIP1 kinase complex-dependent 2–4 necroptosis 5 that follows DR-activation as well as a RIP3-dependent, RIP1-independent necrotic pathway that has emerged as a host defense mechanism against murine cytomegalovirus (MCMV) 6. Disruption of Casp8 expression leads to embryonic lethality in mice between E10.5 and E11.5 7. Thus, Casp8 may naturally hold alternative RIP3-dependent death pathways in check in addition to its role promoting apoptosis. We find that RIP3 is responsible for the midgestational death of Casp8-deficient embryos. Remarkably, Casp8−/−Rip3−/− double mutant mice are viable and mature into fertile adults with a full immune complement of myeloid and lymphoid cell types. 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.
Related Links	http://dx.doi.org/10.1038/nature09857
Ending Page	372
Page Count	5
Starting Page	368
File Format	PDF
ISSN	00280836
e-ISSN	14764687
Journal	Nature
Issue Number	7338
Volume Number	471
Language	English
Publisher Date	2011-03-17
Access Restriction	Open
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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