Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

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. Species laboratory mouse Generation +pN1 Generation Definitions   Donating Investigator Bernard Malissen,   Centre d'immunologie de Marseille Luminy

Description
Lat^fl-dtr mutant mice contain a loxP site downstream from exon 1, and an internal ribosome entry site (IRES), a human diphtheria toxin receptor, and an enhanced green fluorescent protein (EGFP) followed by a second loxP site downstream of the internal stop codon of the linker for activation of T cells (Lat) gene. Homozygotes are viable, fertile, and normal in size. LAT is a transmembrane protein expressed in natural killer (NK) cells, mast cells, platelets, megakaryocytes, and T lymphocytes of the thymus and peripheral lymphoid tissues. Following T cell receptor (TCR) activation, LAT phosphorylation triggers downstream T cell-specific signaling pathways. These mice express 1.2-fold less LAT than control mice, with no apparent affect on T cell function. Diphtheria toxin (DT) administration results in acute ablation of LAT-expressing T thymocytes in the thymus and peripheral lymphoid tissues. When these mutant mice are bred to mice that express Cre recombinase, the resulting offspring will have exons 2-12, as well as the IRES-DTREGFP cassette, deleted in the cre-expressing tissue, resulting in inactivation of Lat gene function. Upon deletion of the two Lat^fl-dtr alleles, cells become resistant to DT and can be thereby enriched. These mice may be useful for studying the TCR signaling cascade and T cell homeostasis.

Development
The Lat^fl-dtr targeting vector was designed to insert a loxP site downstream from exon 1, and an internal ribosome entry site (IRES), a human diphtheria toxin receptor, and an enhanced green fluorescent protein (EGFP), followed by a loxP-flanked neomycin (neo) resistance cassette, downstream of the internal stop codon of the linker for activation of T cells (Lat) gene. This construct was injected into 129S2/SvPas-derived CK35 embryonic stem (ES) cells. Correctly targeted ES cells were transiently transfected with a GFPcre expression plasmid to delete the neo cassette and label cells containing recombined DNA with GFP. Resulting ES cells contained multiple gene rearrangments; intact floxed-exons 2-12 and IRES-DTREGFP cassette, intact floxed-neo cassette, or removal of exons 2-12, the IRES-DTREGFP cassette, and the neo cassette. Correctly targeted, GFP-labeled, ES cells, containing the floxed-exons and the IRES-DTREGFP cassette, were injected into BALB/c blastocysts and resulting chimeric males were bred with C57BL/6 females. These mice were then backcrossed to C57BL/6J mice for at least 5 generations. Upon arrival at The Jackson Laboratory, mice were bred to C57BL/6J inbred mice (Stock No. 000664) for at least one generation.

Control Information

	Control
	000664 C57BL/6J	(approximate)
Considerations for Choosing Controls

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Lat^tm6(DTR)Mal/Lat^tm6(DTR)Mal

        involves: 129S2/SvPas * C57BL/6   (conditional)

• immune system phenotype
• abnormal T cell activation
  • CD4⁺ T cells were first transfected with a cre recombinase vector and then treated with dipthera toxin so that surviving T cells did not produce LAT protein   (MGI Ref ID J:151840)
  • these T cells show almost no intracellular calcium mobilization and no ERK -1 and -2 activation after TCR engagement   (MGI Ref ID J:151840)
  • T cells also fail to produce IFN-gamma after activation   (MGI Ref ID J:151840)
• abnormal T-helper 2 physiology
  • CD4⁺ T cells were first transfected with a cre recombinase vector and then treated with dipthera toxin so that surviving T cells do not produce LAT protein   (MGI Ref ID J:151840)
  • when activated and transferred into T cell deficient hosts, these T cells cause splenomegaly, lymphadenopathy and secrete high levels of IL-4   (MGI Ref ID J:151840)
• decreased interferon-gamma secretion
  • CD4⁺ T cells transfected with a cre recombinase vector and treated with dipthera toxin do not produce IFN-gamma upon activation   (MGI Ref ID J:151840)
• hematopoietic system phenotype
• abnormal T cell activation
  • CD4⁺ T cells were first transfected with a cre recombinase vector and then treated with dipthera toxin so that surviving T cells did not produce LAT protein   (MGI Ref ID J:151840)
  • these T cells show almost no intracellular calcium mobilization and no ERK -1 and -2 activation after TCR engagement   (MGI Ref ID J:151840)
  • T cells also fail to produce IFN-gamma after activation   (MGI Ref ID J:151840)
• cellular phenotype
• abnormal T cell activation
  • CD4⁺ T cells were first transfected with a cre recombinase vector and then treated with dipthera toxin so that surviving T cells did not produce LAT protein   (MGI Ref ID J:151840)
  • these T cells show almost no intracellular calcium mobilization and no ERK -1 and -2 activation after TCR engagement   (MGI Ref ID J:151840)
  • T cells also fail to produce IFN-gamma after activation   (MGI Ref ID J:151840)

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Cell Biology Research
Signal Transduction

Hematological Research
Mast Cell Deficiency

Immunology, Inflammation and Autoimmunity Research
Immunodeficiency
      T cell deficiency
T Cell Receptor Signaling Defects

Internal/Organ Research
Lymphoid Tissue Defects
      T cell deficiency

Research Tools
Cre-lox System
      loxP-flanked Sequences
Immunology and Inflammation Research
      Mast Cell Deficiency

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Lattm6(DTR)Mal
Allele Name		targeted mutation 6, Bernard Malissen
Allele Type		Targeted (Floxed/Frt)
Common Name(s)		LatDTR; Lattm6Mal;
Mutation Made By		Bernard Malissen,   Centre d'immunologie de Marseille Luminy
Strain of Origin		129S2/SvPas
Gene Symbol and Name		Lat, linker for activation of T cells
Chromosome		7
Gene Common Name(s)		LAT1; pp36;
Molecular Note		A loxP site was inserted into intron 1 and a pIRES2-DTR-EGFP-loxP-Neo-loxP cassette was 114 bp downstream of the stop codon in exon 12. Correctly targeted ES cells were transiently transfected with cre recombinase and clones that had just the neomycin cassette removed were selected for mouse production. This left a human dipthera toxin receptor and an EGFP cassette in the 3' untranslated region. Very low levels of EGFP were detected in thymocytes. Thymocytes and T cells from homozygous mice expressedapproximately 1.2-fold less LAT molecules than those of wild-type mice. T cell function was not impaired in these mice. Cre-recombinase expression will remove most of the coding sequence and the DTR-expression cassette from the locus. [MGI Ref ID J:138401] [MGI Ref ID J:151840]

Genotyping

Genotyping Information

Genotyping Protocols

Lat^tm6(DTR)Mal,

Separated MCA

Lat^tm6(DTR)Mal, Separated PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Helft J; Jacquet A; Joncker NT; Grandjean I; Dorothee G; Kissenpfennig A; Malissen B; Matzinger P; Lantz O. 2008. Antigen-specific T-T interactions regulate CD4 T-cell expansion. Blood 112(4):1249-58. [PubMed: 18539897]  [MGI Ref ID J:138401]

Additional References

Lat^tm6(DTR)Mal related

Mingueneau M; Roncagalli R; Gregoire C; Kissenpfennig A; Miazek A; Archambaud C; Wang Y; Perrin P; Bertosio E; Sansoni A; Richelme S; Locksley RM; Aguado E; Malissen M; Malissen B. 2009. Loss of the LAT adaptor converts antigen-responsive T cells into pathogenic effectors that function independently of the T cell receptor. Immunity 31(2):197-208. [PubMed: 19682930]  [MGI Ref ID J:151840]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200.

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, homozygous mice may be bred together.

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

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

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The Jackson Laboratory's Genotype Promise

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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Terms of Use

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