All Phenotypes Csnk1g2<em1Xidw> MGI Mouse

increased susceptibility to induced morbidity/mortality ( J:298682 )

• although mice apperar normal, they die within 18 hr after a single i.p. injection of murine TNF (300 ug/kg), about 6 hours faster than TNF-treated wild-type controls

early reproductive senescence ( J:298682 )

• males exhibit a significantly enhanced necroptosis response and premature aging of their testis relative to wild-type males

• although all young males are able to produce progeny at 2 months of age, only 1 of 12 males was able to produce pups at 12 months of age versus 10 of 12 of wild-type males

• all signs of premature male reproductive system aging are restored when mice are fed a RIPK1 kinase inhibitor (RIPA-56)-containing diet and all (10 of 10) mice fed with RIPA-56 were able to produce pups when paired with young (10-week-old) female partners at 12 months of age

increased body weight ( J:298682 )

• male whole body weight is normal at 2 months of age but significantly higher than that in age-matched wild-type controls at 12 months of age (45 g versus 37 g, respectively)

• feeding 2-month old mice with a RIPA-56-containing diet for 10 months restores body weight to wild-type values at 12 months of age

increased seminal vesicle weight ( J:298682 )

• at 12 months of age, seminal vesicle weight is ~1 g, a 10-fold increase from when mice are 2 months old, and ~2-fold higher than that in 12-month old wild-type controls

• feeding 2-month old mice with a RIPA-56-containing diet for 10 months restores seminal vesicle weight to wild-type values at 12 months of age

abnormal seminiferous tubule morphology ( J:298682 )

• at 12 months of age, ~31% of seminiferous tubules appear empty relative to only ~2% empty tubules seen in age-matched wild-type controls

• at 12 months, the number of phospho-Serine345-MLK (phosho-MLKL)-positive cells per field of view is significantly higher than that in wild-type tubules, indicating increased necroptosis activation

• feeding 2-month old mice with a RIPA-56-containing diet for 10 months drops the % of empty tubules to 4% while the necroptosis activation marker phosho-MLKL is reduced to almost non-detectable levels

small testis ( J:298682 )

• at 12 months of age, testis size is significantly smaller than that in age-matched wild-type controls

decreased testis weight ( J:298682 )

• at 12 months of age, testis weight is significantly lower than that in age-matched wild-type controls

• feeding 2-month old mice with a RIPA-56-containing diet for 10 months restores testis weight to wild-type values at 12 months of age

early reproductive senescence ( J:298682 )

• males exhibit a significantly enhanced necroptosis response and premature aging of their testis relative to wild-type males

• although all young males are able to produce progeny at 2 months of age, only 1 of 12 males was able to produce pups at 12 months of age versus 10 of 12 of wild-type males

• all signs of premature male reproductive system aging are restored when mice are fed a RIPK1 kinase inhibitor (RIPA-56)-containing diet and all (10 of 10) mice fed with RIPA-56 were able to produce pups when paired with young (10-week-old) female partners at 12 months of age

decreased circulating testosterone level ( J:298682 )

• at 12 months of age, serum testosterone levels are significantly lower than those in age-matched wild-type controls

• feeding 2-month old mice with a RIPA-56-containing diet for 10 months restores serum testosterone levels to levels seen in young mice at 3 months of age

increased circulating follicle stimulating hormone level ( J:298682 )

• at 12 months of age, serum FSH levels are significantly higher than those in age-matched wild-type controls

• feeding 2-month old mice with a RIPA-56-containing diet for 10 months mitigates serum FSH levels to levels seen in young mice at 3 months of age

increased circulating luteinizing hormone level ( J:298682 )

• at 12 months of age, serum LH levels are significantly higher than those in age-matched wild-type controls

• feeding 2-month old mice with a RIPA-56-containing diet for 10 months mitigates serum LH levels to levels seen in young mice at 3 months of age

abnormal circulating protein level ( J:298682 )

• at 12 months of age, serum sex hormone-binding globulin (SHBG) levels are significantly higher than those in age-matched wild-type controls

• feeding 2-month old mice with a RIPA-56-containing diet for 10 months mitigates serum SHBG levels to levels seen in young mice at 3 months of age

abnormal response/metabolism to endogenous compounds ( J:298682 )

• mice exhibit accelerated TNF-induced systematic sepsis and lethality relative to TNF-treated wild-type controls

increased sensitivity to induced cell death ( J:298682 )

• bone marrow-derived macrophages (BMDMs) show enhanced cell death when treated with necroptosis-inducing agents, including T/S/Z (a combination of TNF, a Smac mimetic, and a pan-caspase inhibitor Z-VAD-fmk), TRAIL/S/Z (TNF-related apoptosis-inducing ligand plus a Smac mimetic and z-VAD), or LPS/S/Z (LPS plus a Smac mimetic and z-VAD), relative to wild-type BMDMs

• primary testis cells isolated from the seminiferous tubules of 2-month old mice show significantly more cell death when treated with necroptosis stimuli T/S/Z than wild-type testis cells