Allele Symbol: Map3k8M1Btlr
Name: mutation 1, Bruce Beutler
Alteration at locus: Chemically Induced
Gene Symbol: Map3k8
Name: mitogen-activated protein kinase kinase kinase 8
Alteration at locus: Chemically Induced
ES Cell Line: Not Applicable
Homozygous phenotype: The Sluggish
phenotype was identified in a screen of homozygous ENU-induced G3 mutant
mice for altered responses to Toll-like receptor (TLR) ligands.
Peritoneal macrophages from Sluggish homozygotes did not produce tumor
necrosis factor (TNF)-α in response to the TLR2/6 ligands MALP2
(macrophage-activating lipopeptide 2) and peptidoglycan, or to the TLR9
ligand CpG DNA. These macrophages also exhibited a partially reduced
TNF-α response to other TLR ligands, such as the TLR4 ligand
lipopolysaccharide (LPS), the TLR1/2 ligand Pam3CSK4 (a triacyl
lipopeptide), the TLR7 ligand resiquimod (a ssRNA mimetic), and the TLR3
ligand poly I:C (a dsRNA mimetic). The TNF-α response to TLR7 is
greatly reduced, while the responses to TLR4, TLR1/2, and TLR3 are
intermediate. In addition, the interferon (IFN) α/β response
to TLR7 and TLR9 signaling was abolished as was the production of IL-
1β induced by LPS, but the interferon response to LPS and poly I:C
was normal. The defect in the TNF-α response to TLR signaling is
likely to be one of post-transcriptional proteolytic processing as normal
levels of intracellular TNF-α are observed in MALP2, peptidoglycan,
and CpG stimulated Sluggish macrophages. Peritoneal macrophages from
Sluggish homozygotes showed normal resistance to mouse cytomegalovirus
(MCMV) and normal restriction of GFP expression when infected by a non-
replicating recombinant Adenovirus 5 vector, but failed to produce TNF-α in response to viral infection. Sluggish homozygous mice have
impaired natural killer (NK) cell cyotoxicity in vivo as measured by
reduced clearance of MHC class 1-deficient cells.
A quarter of the expected number of heterozygous and very few homozygous Sluggish animals are born, suggesting that the Sluggish mutation affects embryonic survival. The stage at which death occurs is unknown. Surviving Sluggish homozygous animals exhibit no visible phenotypic defects, are viable, and can breed.
Heterozygous phenotype: Heterozygous Sluggish animals displayed a partial TNF-α response to TLR2/6 signaling and reduced numbers survive birth.
Strain of Origin: C57BL/6J
Strain genetic background: C57BL/6J
Strain Development: The sluggish mutation was induced by ENU mutagenesis on the C57BL/6J background, and was discovered in G3 animals. All subsequent crosses to maintain strain were on a C57BL/6J background.
Suggested Control Mice:
Donor: Bruce Beutler, M.D., The Scripps Research Institute
Limited quantities of breeder mice (recovered litter) are available from a cryoarchive; recovered litter usually available to ship in 3 to 4 months.
Fee/unit (US $)
|Litter||Recovered litter1; additional fees for any special requests.|
|Aliquot||Approximate quantity3: 20-40 embryos / aliquot|
1 The distribution fee covers the expense of resuscitating mice from the cryo-archive; you will receive the resulting litter. The litter will contain at minimum one mutant carrier; the actual number of animals and the gender and genotype ratios will vary. (Typically, multiple breeder pairs can be established from the recovered litter.) Prior to shipment, the MMRRC will provide information about the animals recovered. If you anticipate or find that you need to request specific genotypes, genders or quantities of mice in excess of what is likely from a resuscitated litter, you may discuss available options and pricing with the supplying MMRRC facility.
2 An aliquot is one straw or vial with sufficient sperm to recover at least one litter of mice, as per provided protocols, when performed at the MMRRC facility. The MMRRC makes no guarantee concerning the success of these procedures when performed outside the MMRRC facilities.
3 An aliquot contains a sufficient number of embryos (in one or more vials and based on the transfer success rate of the MMRRC facility) to transfer to at least two recipients. The MMRRC makes no guarantee concerning embryo transfer success experienced in the recipient investigator's laboratory. Neither gender nor genotype ratios are guaranteed.
To request material from the MMRRC: Please fill out our on-line request form (accessible from the catalog search results page, or click the Request this Strain button in the fees section). If you have questions or need assistance completing this form, you may call Customer Service at (800) 910-2291 (in USA or Canada) or (530) 757-5710 (international calls). Before you call, please have with you: the MMRRC item number, quantity needed, Bill-to and Ship-to contact information.