Necroptotic Cell Death Signaling and Execution Pathway: Lessons from Knockout Mice

Table 1

Summary of phenotypes of double- and triple-knockout mice ablated for genes that regulate apoptotic and necroptotic cell death pathways.

Crossed; mice	ripk1−/−; die postnatal; days 1-2	ripk3−/−; viable	mlkl−/−; viable	ripk1−/−; ripk3−/−; die postnatal day 4	ripk1−/−; mlkl−/−; die postnatal day 4
casp8−/−; Embryonic lethal	Embryonic lethal	Viable	Embryonic lethal	Viable; fertile	Die postnatal day 4
flip−/−; Embryonic lethal	Embryonic lethal	Embryonic lethal	Embryonic lethal	?	?
fadd−/−; Embryonic lethal	Embryonic lethal	Viable; lympha-denopathy	Embryonic; lethal	Viable; fertile	Viable; fertile
casp8−/−; fadd−/−; Embryonic lethal	Embryonic lethal	Viable	Embryonic lethal	Viable; fertile	?
flip−/−; fadd−/−; Embryonic lethal	Embryonic lethal	Viable; lympha-denopathy; splenomegaly	Embryonic lethal	Viable; fertile	?
bax−/−; bak−/−; viable (10%)	Embryonic lethal	?	?	?	?
cypd−/−; viable	Embryonic lethal	Viable; partial protection of cardiac ischemia	Viable	?	?

Summary of knockout mice models of apoptosis and necroptosis genes for which the phenotypes reveal a critical role in development, physiology, and homeostasis. Caspase-8, FLIP, and FADD proteins have pivotal roles in the death inducing signaling complex that regulate apoptosis FLIP deficiency causes both massive apoptosis and necrosis. Knockout mice for caspase-8, Casp-8−/−, FADD, and Fadd−/− or double knockouts for both show an embryonically lethal phenotype due to uncontrolled necrosis. Knockout mice for RIPK1, Ripk1−/−, die at birth of systemic inflammation whereas Ripk3−/− mice are normal but are resistant to proinflammatory stimuli. Mlkl−/− mice are anatomically normal, viable, and fertile. Triple knockouts mice Fadd−/− Flip−/− Ripk3−/− have a normal cell-death pathway and develop to normal birth because of absence of necrosis and apoptosis which are modulated by caspase-8. Casp8−/− Mlkl−/− double knockout mice are normal and resistant to TNF-induced necroptosis. Bax−/− Bak−/− double knockout mice develop perinatal lethality and only 10% survive into adulthood, and these mice develop splenomegaly and lymphadenopathy. The question mark indicates possible or still unknown.