RIP1 is an adaptor kinase originally identified as being able to associate with 
TNFR1 and Fas, and is later shown to be involved in signaling induced by TLRs. 
Major signaling pathways regulated by RIP1 include necroptosis, apoptosis, and 
pro-survival/inflammation NF-κB activation. Previous studies show that RIP1 
deficiency has no effect on mouse embryogenesis, but blocks postnatal 
development. This phenotype could not readily be explained, since mice lacking 
TNFR1, Fas, or TLRs show no apparent developmental defect. Certain types of 
RIP1-deficient cells are hypersensitive to TNF-induced apoptosis. However, in 
our previous study, deletion of the apoptotic adaptor protein, FADD, provides 
marginal improvement of postnatal development of rip1 (-/-) mice. Remarkably, 
the current data shows that haploid insufficiency of RIP3, a known mediator of 
necroptosis, allowed survival of rip1 (-/-) fadd (-/-) mice beyond weaning age, 
although the resulting rip1(-/-)fadd(-/-) rip3(+/-) mice were significant 
smaller in size and weight. Moreover, complete absence of RIP3 further improved 
postnatal development of the resulting rip1 (-/-) fadd (-/-) rip3 (-/-) mice, 
which display normal size and weight. In such triple knockout (TKO) mice, 
lymphocytes underwent normal development, but progressively accumulated as mice 
age. This lymphoproliferative (lpr) disease in TKO mice is, however, less severe 
than that of fadd(-/-)rip3 (-/-) double knockout mice. In total, the data show 
that the postnatal developmental defect in rip1 (-/-) mice is due in part to 
FADD-mediated apoptosis as well as RIP3-dependent necroptosis. Moreover, the 
function of RIP1 contributes to development of lpr diseases.