Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Mating System Homozygote x Homozygote         (Female x Male)   01-MAR-06 Species laboratory mouse Generation N12+N1F13N2F6 (27-NOV-11) Generation Definitions   Donating Investigator Sergei Nedospasov,   NCI-FCRDC

Description
Mice that are homozygous for the targeted mutation are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. No gene product (mRNA) from any of the three targeted genes is detected by RT-PCR analysis of concanavalin-A activated splenocytes. Leukocyte numbers in the spleen, blood and peritoneal cavity are increased 2 to 3 fold. Homozygous mice have abnormal lymphoid development and do not develop Peyer's patches or lymph nodes. Spleen microarchitecture is abnormal. No germinal center forms in the spleen following antigenic challenge. Mutant mice display defective antibody responses. This strain displays a phenotype more severe than the phenotypes exhibited by any of the single targeted mutation strains of the genes and may be useful in studies of peripheral lymphoid organ development, and antibody response to T cell dependent antigens.

Development
A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes, and four loxP sites, flanking each of the three genes, was used to disrupt 8.4 kb of sequence encoding all of the Tnf gene and the last exons of the Lta and Ltb genes. The construct was electroporated into 129P2/OlaHsd derived E14.1 embryonic stem (ES) cells. Correctly targeted ES cells were transiently transfected with a cre expression plasmid for the purpose of removing the selectable marker cassette. ES cells that had successfully undergone Cre-mediated recombination and no longer retained the cassette were injected into C57BL/6 blastocysts. The donating investigator reported that the resulting chimeric animals were crossed to C57BL/6 mice, and then backcrossed to for 12 generations (see SNP note below).

A 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at The Jackson Laboratory Repository. While the 27 markers throughout the genome suggested a C57BL/6 genetic background, 3 of 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating. These data suggest the mice sent to The Jackson Laboratory Repository were on a mixed C57BL/6J ; C57BL/6N genetic background.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Lta

002258	B6.129S2-Ltatm1Dch/J
002257	B6;129S2-Ltatm1Dch/J
005579	C57BL/6J-Ltahlb382/J

View Strains carrying other alleles of Lta     (3 strains)

Strains carrying other alleles of Ltb

003530	B6;129-Ltbtm1Flv/J
005112	STOCK Ltb/Tnftm1.1Dvk/J

View Strains carrying other alleles of Ltb     (2 strains)

Strains carrying other alleles of Tnf

005540	B6.129S-Tnftm1Gkl/J
003008	B6;129S-Tnftm1Gkl/J
007082	CByJ.129S(B6)-Tnftm1Gkl/J
005112	STOCK Ltb/Tnftm1.1Dvk/J

View Strains carrying other alleles of Tnf     (4 strains)

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Ltb/Tnf/Lta^tm1Dvk/Ltb/Tnf/Lta^tm1Dvk

        involves: C57BL/6

• hematopoietic system phenotype
• decreased spleen white pulp amount
  • percentage of splenic white pulp is lower than in wild-type, Ltb, the two Lta mutant lines, Ltb or Ltbr knockouts   (MGI Ref ID J:109621)
• immune system phenotype
• decreased spleen white pulp amount
  • percentage of splenic white pulp is lower than in wild-type, Ltb, the two Lta mutant lines, Ltb or Ltbr knockouts   (MGI Ref ID J:109621)

Ltb/Tnf/Lta^tm1Dvk/Ltb/Tnf/Lta^tm1Dvk

        B6.Cg-Ltb/Tnf/Lta^tm1Dvk

• immune system phenotype
• abnormal class switch recombination
  • specific IgG antibodies are almost undetectable in SRBC immunized mutants, indicating defective class switching   (MGI Ref ID J:80616)
• abnormal spleen morphology
  • spleen architecture is severely disturbed   (MGI Ref ID J:80616)
  • distribution of lymphocytes and their functional compartmentalization are severely disorganized in the spleen, with IgD+ B cells scattered along red and white pulp and T cells mostly condensed around central arterioles   (MGI Ref ID J:80616)
• • abnormal spleen B cell follicle morphology
    • absence of polarized B-cell follicles   (MGI Ref ID J:80616)
  • • absent spleen germinal center
      • do not form germinal centers   (MGI Ref ID J:80616)
  • absent spleen marginal zone   (MGI Ref ID J:80616)
  • decreased spleen white pulp amount
    • gradual reduction of white pulp size   (MGI Ref ID J:80616)
• absent Peyer's patches   (MGI Ref ID J:80616)
• absent axillary lymph nodes   (MGI Ref ID J:80616)
• absent brachial lymph nodes   (MGI Ref ID J:80616)
• absent inguinal lymph nodes   (MGI Ref ID J:80616)
• absent lymph nodes   (MGI Ref ID J:80616)
• absent mesenteric lymph nodes   (MGI Ref ID J:80616)
• absent popliteal lymph nodes   (MGI Ref ID J:80616)
• decreased IgG level
  • specific IgG antibodies are almost undetectable in SRBC immunized mutants   (MGI Ref ID J:80616)
• increased leukocyte cell number
  • 2-3 fold increase in the number of leukocytes in the spleen, blood, and peritoneal cavity   (MGI Ref ID J:80616)
• increased susceptibility to bacterial infection
  • increased susceptibility to Listeria monocytogenes infections, with mutants dying by day 8 while wild-type mice survive   (MGI Ref ID J:80616)
  • increased susceptibility to Salmonella enterica infection   (MGI Ref ID J:80616)
• hematopoietic system phenotype
• abnormal class switch recombination
  • specific IgG antibodies are almost undetectable in SRBC immunized mutants, indicating defective class switching   (MGI Ref ID J:80616)
• abnormal spleen morphology
  • spleen architecture is severely disturbed   (MGI Ref ID J:80616)
  • distribution of lymphocytes and their functional compartmentalization are severely disorganized in the spleen, with IgD+ B cells scattered along red and white pulp and T cells mostly condensed around central arterioles   (MGI Ref ID J:80616)
• • abnormal spleen B cell follicle morphology
    • absence of polarized B-cell follicles   (MGI Ref ID J:80616)
  • • absent spleen germinal center
      • do not form germinal centers   (MGI Ref ID J:80616)
  • absent spleen marginal zone   (MGI Ref ID J:80616)
  • decreased spleen white pulp amount
    • gradual reduction of white pulp size   (MGI Ref ID J:80616)
• increased leukocyte cell number
  • 2-3 fold increase in the number of leukocytes in the spleen, blood, and peritoneal cavity   (MGI Ref ID J:80616)
• cellular phenotype
• abnormal class switch recombination
  • specific IgG antibodies are almost undetectable in SRBC immunized mutants, indicating defective class switching   (MGI Ref ID J:80616)

Ltb/Tnf/Lta^tm1Dvk/Ltb/Tnf/Lta^tm1Dvk

        B6.Cg-Ltb/Tnf/Lta^tm1Dvk

• immune system phenotype
• abnormal class switch recombination
  • specific IgG antibodies are almost undetectable in SRBC immunized mutants, indicating defective class switching   (MGI Ref ID J:80616)
• abnormal spleen morphology
  • spleen architecture is severely disturbed   (MGI Ref ID J:80616)
  • distribution of lymphocytes and their functional compartmentalization are severely disorganized in the spleen, with IgD+ B cells scattered along red and white pulp and T cells mostly condensed around central arterioles   (MGI Ref ID J:80616)
• • abnormal spleen B cell follicle morphology
    • absence of polarized B-cell follicles   (MGI Ref ID J:80616)
  • • absent spleen germinal center
      • do not form germinal centers   (MGI Ref ID J:80616)
  • absent spleen marginal zone   (MGI Ref ID J:80616)
  • decreased spleen white pulp amount
    • gradual reduction of white pulp size   (MGI Ref ID J:80616)
• absent Peyer's patches   (MGI Ref ID J:80616)
• absent axillary lymph nodes   (MGI Ref ID J:80616)
• absent brachial lymph nodes   (MGI Ref ID J:80616)
• absent inguinal lymph nodes   (MGI Ref ID J:80616)
• absent lymph nodes   (MGI Ref ID J:80616)
• absent mesenteric lymph nodes   (MGI Ref ID J:80616)
• absent popliteal lymph nodes   (MGI Ref ID J:80616)
• decreased IgG level
  • specific IgG antibodies are almost undetectable in SRBC immunized mutants   (MGI Ref ID J:80616)
• increased leukocyte cell number
  • 2-3 fold increase in the number of leukocytes in the spleen, blood, and peritoneal cavity   (MGI Ref ID J:80616)
• increased susceptibility to bacterial infection
  • increased susceptibility to Listeria monocytogenes infections, with mutants dying by day 8 while wild-type mice survive   (MGI Ref ID J:80616)
  • increased susceptibility to Salmonella enterica infection   (MGI Ref ID J:80616)
• hematopoietic system phenotype
• abnormal class switch recombination
  • specific IgG antibodies are almost undetectable in SRBC immunized mutants, indicating defective class switching   (MGI Ref ID J:80616)
• abnormal spleen morphology
  • spleen architecture is severely disturbed   (MGI Ref ID J:80616)
  • distribution of lymphocytes and their functional compartmentalization are severely disorganized in the spleen, with IgD+ B cells scattered along red and white pulp and T cells mostly condensed around central arterioles   (MGI Ref ID J:80616)
• • abnormal spleen B cell follicle morphology
    • absence of polarized B-cell follicles   (MGI Ref ID J:80616)
  • • absent spleen germinal center
      • do not form germinal centers   (MGI Ref ID J:80616)
  • absent spleen marginal zone   (MGI Ref ID J:80616)
  • decreased spleen white pulp amount
    • gradual reduction of white pulp size   (MGI Ref ID J:80616)
• increased leukocyte cell number
  • 2-3 fold increase in the number of leukocytes in the spleen, blood, and peritoneal cavity   (MGI Ref ID J:80616)
• cellular phenotype
• abnormal class switch recombination
  • specific IgG antibodies are almost undetectable in SRBC immunized mutants, indicating defective class switching   (MGI Ref ID J:80616)

Ltb/Tnf/Lta^tm1Dvk/Ltb/Tnf/Lta^tm1Dvk

        B6.Cg-Ltb/Tnf/Lta^tm1Dvk

• immune system phenotype
• abnormal class switch recombination
  • specific IgG antibodies are almost undetectable in SRBC immunized mutants, indicating defective class switching   (MGI Ref ID J:80616)
• abnormal spleen morphology
  • spleen architecture is severely disturbed   (MGI Ref ID J:80616)
  • distribution of lymphocytes and their functional compartmentalization are severely disorganized in the spleen, with IgD+ B cells scattered along red and white pulp and T cells mostly condensed around central arterioles   (MGI Ref ID J:80616)
• • abnormal spleen B cell follicle morphology
    • absence of polarized B-cell follicles   (MGI Ref ID J:80616)
  • • absent spleen germinal center
      • do not form germinal centers   (MGI Ref ID J:80616)
  • absent spleen marginal zone   (MGI Ref ID J:80616)
  • decreased spleen white pulp amount
    • gradual reduction of white pulp size   (MGI Ref ID J:80616)
• absent Peyer's patches   (MGI Ref ID J:80616)
• absent axillary lymph nodes   (MGI Ref ID J:80616)
• absent brachial lymph nodes   (MGI Ref ID J:80616)
• absent inguinal lymph nodes   (MGI Ref ID J:80616)
• absent lymph nodes   (MGI Ref ID J:80616)
• absent mesenteric lymph nodes   (MGI Ref ID J:80616)
• absent popliteal lymph nodes   (MGI Ref ID J:80616)
• decreased IgG level
  • specific IgG antibodies are almost undetectable in SRBC immunized mutants   (MGI Ref ID J:80616)
• increased leukocyte cell number
  • 2-3 fold increase in the number of leukocytes in the spleen, blood, and peritoneal cavity   (MGI Ref ID J:80616)
• increased susceptibility to bacterial infection
  • increased susceptibility to Listeria monocytogenes infections, with mutants dying by day 8 while wild-type mice survive   (MGI Ref ID J:80616)
  • increased susceptibility to Salmonella enterica infection   (MGI Ref ID J:80616)
• hematopoietic system phenotype
• abnormal class switch recombination
  • specific IgG antibodies are almost undetectable in SRBC immunized mutants, indicating defective class switching   (MGI Ref ID J:80616)
• abnormal spleen morphology
  • spleen architecture is severely disturbed   (MGI Ref ID J:80616)
  • distribution of lymphocytes and their functional compartmentalization are severely disorganized in the spleen, with IgD+ B cells scattered along red and white pulp and T cells mostly condensed around central arterioles   (MGI Ref ID J:80616)
• • abnormal spleen B cell follicle morphology
    • absence of polarized B-cell follicles   (MGI Ref ID J:80616)
  • • absent spleen germinal center
      • do not form germinal centers   (MGI Ref ID J:80616)
  • absent spleen marginal zone   (MGI Ref ID J:80616)
  • decreased spleen white pulp amount
    • gradual reduction of white pulp size   (MGI Ref ID J:80616)
• increased leukocyte cell number
  • 2-3 fold increase in the number of leukocytes in the spleen, blood, and peritoneal cavity   (MGI Ref ID J:80616)
• cellular phenotype
• abnormal class switch recombination
  • specific IgG antibodies are almost undetectable in SRBC immunized mutants, indicating defective class switching   (MGI Ref ID J:80616)

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Ltb/Tnf/Ltatm1Dvk
Allele Name		targeted mutation 1, Dmitry V Kuprash
Allele Type		Targeted (knock-out)
Common Name(s)		TNF/LTDelta3; Tnfabc-;
Mutation Made By		Dmitry Kuprash,   Engelhardt Inst of Molecular Biology
Gene Symbol and Name		Lta, lymphotoxin A
Chromosome		17
Gene Common Name(s)		LT; LT-[a]; LT-alpha; LT[a]; LTalpha; Ltx; TNF beta; TNF-beta; TNFB; TNFSF1; Tnfb; Tnfsf1b; heart, lung and blood 382; hlb382; lymphotoxin; lymphotoxin alpha; tumor necrosis factor beta;
Associated Marker Note		Affected-Count: 2Af1-Gene: MGI:104796 Af2-Gene: MGI:104798
Molecular Note		An 8.4 kb region, containing the entire Tnf gene and the last coding exons of the Lta and Ltb genes, was deleted by cre mediated recombination of surrounding loxP sites inserted within Lta and Ltb via homologous recombiantion. Partial coding regions of Lta and Ltb were left intact separtated by a single loxP site, however RT-PCR analysis of homozygous mutant splenocytes activated by concanavalin A indicated an absence of transcript from each locus. [MGI Ref ID J:80616]
Gene Symbol and Name		Tnf, tumor necrosis factor
Chromosome		17
Gene Common Name(s)		DIF; RATTNF; TNF alpha; TNF-alpha; TNFA; TNFSF2; TNFalpha; Tnfa; Tnfsf1a; tumor necrosis factor, alpha; tumor necrosis factor-alpha;
Gene Symbol and Name		Ltb, lymphotoxin B
Chromosome		17
Gene Common Name(s)		AI662801; LTbeta; TNFC; TNFSF3; Tnfc; expressed sequence AI662801; lymphotoxin beta; p33; tumor necrosis factor C;

Genotyping

Genotyping Information

Genotyping Protocols

Ltb/Tnf/Lta^tm1Dvk, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Kuprash DV; Alimzhanov MB; Tumanov AV; Grivennikov SI; Shakhov AN; Drutskaya LN; Marino MW; Turetskaya RL; Anderson AO; Rajewsky K; Pfeffer K; Nedospasov SA. 2002. Redundancy in tumor necrosis factor (TNF) and lymphotoxin (LT) signaling in vivo: mice with inactivation of the entire TNF/LT locus versus single-knockout mice. Mol Cell Biol 22(24):8626-34. [PubMed: 12446781]  [MGI Ref ID J:80616]

Additional References

Ltb/Tnf/Lta^tm1Dvk related

Baseta JG; Stutman O. 2000. TNF regulates thymocyte production by apoptosis and proliferation of the triple negative (CD3-CD4-CD8-) subset. J Immunol 165(10):5621-30. [PubMed: 11067918]  [MGI Ref ID J:112282]

Kendall GS; Hirstova M; Horn S; Dafou D; Acosta-Saltos A; Almolda B; Zbarsky V; Rumajogee P; Heuer H; Castellano B; Pfeffer K; Nedospasov SA; Peebles DM; Raivich G. 2011. TNF gene cluster deletion abolishes lipopolysaccharide-mediated sensitization of the neonatal brain to hypoxic ischemic insult. Lab Invest 91(3):328-41. [PubMed: 21135813]  [MGI Ref ID J:169257]

Liepinsh DJ; Grivennikov SI; Klarmann KD; Lagarkova MA; Drutskaya MS; Lockett SJ; Tessarollo L; McAuliffe M; Keller JR; Kuprash DV; Nedospasov SA. 2006. Novel lymphotoxin alpha (LTalpha) knockout mice with unperturbed tumor necrosis factor expression: reassessing LTalpha biological functions. Mol Cell Biol 26(11):4214-25. [PubMed: 16705172]  [MGI Ref ID J:109621]

Maddox DM; Hicks WL; Vollrath D; LaVail MM; Naggert JK; Nishina PM. 2011. An ENU-induced mutation in the Mertk gene (Mertknmf12) leads to a slow form of retinal degeneration. Invest Ophthalmol Vis Sci 52(7):4703-9. [PubMed: 21436282]  [MGI Ref ID J:175587]

Mouchess ML; Arpaia N; Souza G; Barbalat R; Ewald SE; Lau L; Barton GM. 2011. Transmembrane Mutations in Toll-like Receptor 9 Bypass the Requirement for Ectodomain Proteolysis and Induce Fatal Inflammation. Immunity 35(5):721-32. [PubMed: 22078797]  [MGI Ref ID J:178832]

Rebholz B; Haase I; Eckelt B; Paxian S; Flaig MJ; Ghoreschi K; Nedospasov SA; Mailhammer R; Debey-Pascher S; Schultze JL; Weindl G; Forster I; Huss R; Stratis A; Ruzicka T; Rocken M; Pfeffer K; Schmid RM; Rupec RA. 2007. Crosstalk between Keratinocytes and Adaptive Immune Cells in an IkappaBalpha Protein-Mediated Inflammatory Disease of the Skin. Immunity 27(2):296-307. [PubMed: 17692539]  [MGI Ref ID J:124343]

Tumanov AV; Kuprash DV; Mach JA; Nedospasov SA; Chervonsky AV. 2004. Lymphotoxin and TNF produced by B cells are dispensable for maintenance of the follicle-associated epithelium but are required for development of lymphoid follicles in the Peyer's patches. J Immunol 173(1):86-91. [PubMed: 15210762]  [MGI Ref ID J:90815]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX12

Colony Maintenance

Breeding & Husbandry	These mice are considered immunocompromised; SPF conditions are recommended.
Mating System	Homozygote x Homozygote         (Female x Male)   01-MAR-06
Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls

General Supply Notes

• This strain is included in the Induced Mutant Resource Colony collection.
• Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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