Mouse Genome Informatics
hm1
    Tnftm1Ljo/Tnftm1Ljo
B6.129S1-Tnftm1Ljo
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
• one week following surgery to produce cortical controlled impact (CCI) brain injury, 6-9 week-old null mice show significantly less severe memory deficits than brain-injured wild-type controls based on performance scores in the Morris water maze
• at 48 hours after CCI, both injured mutants and controls show significant motor deficits (neuroscores), but those in mutants are less severe than in injured wild-type mice
• at 1 week post-injury, mutants and wild-type mice with CCI display similar neuroscores, and by 3 weeks, wild-type mice show recovery of motor function to wild-type levels whereas Tnf-null injured mice do not display any significant recovery with time
• brain-injured Tnf-null mice perform better than injured wild-type in balance beam and rotarod tests at 48 hours post-injury; by 3 weeks, wild-type mice show significant recovery to uninjured control levels while injured mutants display little recovery of function

nervous system
• by 1 week post-injury, brain-injured wild-type and Tnf-null mice display a well-developed cavity in ipsilateral cortex; at 4 weeks, in injured wild-type mice, cavity does not extend beyond cortex, but in mutants, cavity reaches white matter or may even become confluent with ventricle
• at 1 week, cavity volume is comparable between wild-type and null mice, but by 2 weeks post-injury, mutants show a greater cortical injury cavity volume than wild-type

cellular
• after bleomycin injection, fewer apoptotic inflammatory cells are seen in brochoalveolar lavage fluid (BALF) from Tnf-null lungs compared to wild-type BALF

immune system
• intratracheal injection of bleomycin induces infiltration of inflammatory cells in lungs; infiltration reaches peak at day 7 and decreases from that time point in wild-type, but treated mutants show persistent infiltration beyond day 7 to at least day 35 after injection

respiratory system
• intratracheal injection of bleomycin induces infiltration of inflammatory cells in lungs; infiltration reaches peak at day 7 and decreases from that time point in wild-type, but treated mutants show persistent infiltration beyond day 7 to at least day 35 after injection
• Tnf-null lungs show significantly higher total cell and lymphocyte counts than wild-type at 21 days following intratracheal injection of bleomycin
• inflammatory changes (infiltration by lymphocytes, septal thickening of alveoli, and fibroblast proliferation) subside in wild-type mice by 75 days post-bleomycin treatment but severe infiltration and honeycomb-like structure are still observed in mutant lungs at this time


Mouse Genome Informatics
hm2
    Tnftm1Ljo/Tnftm1Ljo
either: B6.129-Tnftm1Ljo or (involves: 129/Sv * C57BL/6)
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• neutrophil numbers are increased compared to Tnftm1.2Sned homozygotes
• lymphocyte numbers are increased compared to Tnftm1.2Sned homozygotes
• absent primary B cell follicles; however, follicle-associated epithelium and distribution of M cells are normal
• Peyer's patches are fewer in number
• homozygotes are protected from LPS/D-Gal induced shock
• homozygotes show increased sensitivity to systemic and alimentary L. monocytogenes infection

hematopoietic system
• neutrophil numbers are increased compared to Tnftm1.2Sned homozygotes
• lymphocyte numbers are increased compared to Tnftm1.2Sned homozygotes


Mouse Genome Informatics
hm3
    Tnftm1Ljo/Tnftm1Ljo
involves: 129S1/Sv
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

HIstology of liver and spleen from C. parvum-treated wild type and Tnftm1Ljo/Tnftm1Ljo mice

immune system
• absence of polarized B-cell follicles
• mutants fail to develop germinal centers in the spleen following immunization with SRBC (J:41992)
• gradual reduction of white pulp size
• mutants exhibit a deficiency in maturation of normal antibody response to T-cell dependent antigen (SRBC), showing depressed IgG titers but normal IgM titers
• serum TNF levels are reduced in mutants injected with LPS and can not be detected on day 2 of Listeria monocytogenes infection
• the normal uptake of aggregated gamma globulin by follicular dendritic cells in the spleen of immunized mutants is absent
• production of colony-stimulating factor (CSF), specifically granulocyte-macrophage (GM)-CSF, is reduced after i.p. injection of lipopolysaccharide (LPS)
• induction of MCP-1 is reduced in spleens of mutants infected with Listeria monocytogenes
• increased resistance to liver injury after ConA-induced autoimmune hepatitis, with only infiltrating cells but no liver necrosis detected
• mutants are resistant to the lethality of minute doses of lipopolysaccharide (LPS) following D-galactosamine treatment, however at higher concentrations (1200ug), they succumb to illness to the same extent as wild-type (J:41992)
• mutants are resistant to staphylococcal enterotoxin B in the presence of D-gal (J:41992)
• protected from S. aureus enterotoxin B induced toxic shock (J:95684)
• mutants show a delayed (40 days post injection instead of the 10-14 seen in wild-type), but progressive, response to heat-killed Corynebacterium parvum, that, unlike in wild-type, eventually leads to death by 80 days (J:41992)
• increased susceptibility to Salmonella enterica infection (J:80616)
• increased susceptibility to Listeria monocytogenes infections, with mutants dying by day 8 while wild-type mice survive (J:80616)
• loss of resistance against Listeria monocytogenes (J:95684)
• mutants exhibit increased susceptibility to Candida albicans challenge; 100% die by day 7 post-infection

hematopoietic system
• absence of polarized B-cell follicles
• mutants fail to develop germinal centers in the spleen following immunization with SRBC (J:41992)
• gradual reduction of white pulp size
• mutants exhibit a deficiency in maturation of normal antibody response to T-cell dependent antigen (SRBC), showing depressed IgG titers but normal IgM titers

homeostasis/metabolism
• serum TNF levels are reduced in mutants injected with LPS and can not be detected on day 2 of Listeria monocytogenes infection


Mouse Genome Informatics
hm4
    Tnftm1Ljo/Tnftm1Ljo
involves: 129S1/Sv * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• neutrophil numbers are similar in uninfected or infected (during first days of infection) wild-type controls and Tnftm2Jods homozygous mice
• 7 days post-infection, neutrophil cell number assessed by myeloperoxidase activity levels in footpad lesions relative to infected controls; higher percentage of neutrophils are detected in footpads after 7 days
• 40 days post-infection, a higher percentage of neutrophils in lesion are apoptotic compared to infected controls
• levels of IgG2a ins sera are undetectable in infected mutants compared to infected wild-type
• mean percentage of IFN-gamma secreting CD4+ T cells is markedly enhanced (23.6%) in draining lymph nodes
• cellularity is relatively lower than in wild-type C57BL/6 or Tnftm1Jods homozygous mice
• lymph node cells release more IFN-gamma than wild-type cells
• Il-4 secretion upon re-stimulation with L. major is equivalent to wild-type
• 60 days after L. major infection, mutants have much higher numbers of intralesional parasites than infected wild-type C57BL/6
• number of parasitized neutrophils in lesion is significantly higher in mutants than in infected controls 4 hours after i.p. injection of L.major; percentage of proliferating parasites released from neutrophils is significantly greater than seen in infected controls

hematopoietic system
• neutrophil numbers are similar in uninfected or infected (during first days of infection) wild-type controls and Tnftm2Jods homozygous mice
• 7 days post-infection, neutrophil cell number assessed by myeloperoxidase activity levels in footpad lesions relative to infected controls; higher percentage of neutrophils are detected in footpads after 7 days
• 40 days post-infection, a higher percentage of neutrophils in lesion are apoptotic compared to infected controls
• levels of IgG2a ins sera are undetectable in infected mutants compared to infected wild-type

integument
• mice infected with L. major promastigotes are unable to control developing footpad lesion size, exhibiting much larger lesion size than infected wild-type control at >35 days after infection


Mouse Genome Informatics
hm5
    Tnftm1Ljo/Tnftm1Ljo
involves: 129S1/Sv * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
liver/biliary system
N
• mice fed a high cholesterol diet do not develop hepatic steatosis unlike Lta/Tnftm1Eug homozygotes (J:112797)


Mouse Genome Informatics
ht6
    Tnftm1Ljo/Tnf+
involves: 129S1/Sv
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• exhibit increased susceptibility to high-dose LPS lethality
• exhibit delayed resolution of the Corynebacterium parvum induced inflammatory process lipopolysaccharide (LPS) lethality
• exhibit increased susceptibility to Candida albicans challenge; 60% die by 30 days post-infection


Mouse Genome Informatics
cx7
    Nfkb1tm1Bal/Nfkb1tm1Bal
Relatm1Bal/Relatm1Bal
Tnftm1Ljo/Tnftm1Ljo

involves: 129P2/OlaHsd * 129S1/Sv * 129S4/SvJae
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• triple homozygous pups die within 12 hours of birth
• fewer than expected triple homozygous mutants are found at birth

integument
• the epidermis is marginally thinner


Mouse Genome Informatics
cx8
    Reltm1Grd/Reltm1Grd
Relatm1Bal/Relatm1Bal
Tnftm1Ljo/Tnftm1Ljo

involves: 129P2/OlaHsd * 129S1/Sv * 129S4/SvJae
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• triple homozygous pups die within 12 hours of birth

cellular
• transit-amplifying epidermal cells display a delay in G1/S phase progression
• transit-amplifying epidermal cells display reduced proliferation

embryogenesis
• triple homozygous embryos are about 30% smaller compared to littermate controls

growth/size/body
• triple homozygous embryos are about 30% smaller compared to littermate controls

integument
• about a 24 hour delay in hair placode formation is seen compared to control littermates
• at E18 the hair follicles that are present are only rudimentary buds lacking hair shafts
• at E18, 70% fewer hair follicles are present compared to control littermates
• the cells in the basal cell layer are organized differently and the basal cell profile area is reduced by about 33%
• the number of differentiating keratinocytes is reduced
• the epidermis is significantly thinner


Mouse Genome Informatics
cx9
    Relatm1Yuo/Relatm1Yuo
Tnftm1Ljo/Tnftm1Ljo

involves: 129S/SvEv * 129S1/SvEv
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
muscle
• myogenesis is accelerated in myoblasts in cultured mouse embryonic fibroblasts and in vivo
• mice exhibit a decrease in fiber diameter
• mutant mice exhibit a 76% increase in the number of myofibers


Mouse Genome Informatics
cx10
    Relatm1Bal/Relatm1Bal
Tnftm1Ljo/Tnftm1Ljo

involves: 129S1/Sv * 129S4/SvJae * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• Schwann cell apoptosis is increased compared to in wild-type mice 24 hours post-axotomy


Mouse Genome Informatics
cx11
    Tnftm1Ljo/Tnftm1Ljo
Tnip1tm1.1Ama/Tnip1tm1.1Ama

involves: 129S1/Sv * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
N
• mice are born in Mendelian ratio (J:145539)


Mouse Genome Informatics
cx12
    Tnftm1Ljo/Tnf+
Tnip1tm1.1Ama/Tnip1tm1.1Ama

involves: 129S1/Sv * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• fewer than expected mice are born alive