Strain Name:
C57BL/6J-Map3k8m1Btlr/Mmucd
Stock Number:
030499-UCD
Citation ID:
RRID:MMRRC_030499-UCD
Other Names:
Sluggish, C57BL/6J-Map3k8m1Btlr/Mmcd
Major Collection:

Gene Information

Map3k8M1Btlr
Name: mitogen-activated protein kinase kinase kinase 8; mutation 1, Bruce Beutler
Synonyms: sluggish
Type: Allele
Species: Mus musculus (mouse)
Chromosome: 18
Alteration at locus: Chemically Induced
Map3k8
Name: mitogen-activated protein kinase kinase kinase 8
Synonyms: Cot, Tpl2, c-COT, Tpl-2, Cot/Tpl2
Type: Gene
Species: Mus musculus (mouse)
Chromosome: 18
Alteration at locus: Chemically Induced
NCBI: 26410
HGNC: HGNC:6860
Homologene: 3812
Genetic Alterations
The Sluggish mutation was mapped to Chromosome 18, and is a T to A transversion in the acceptor splice site of intron 5 at position 13346 of the Map3k8 gene (Genbank genomic region NC_000084 for linear genomic DNA sequence of Map3k8).
Genotype Determination
Phenotype
Homozygous: 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: Heterozygous Sluggish animals displayed a partial TNF-α response to TLR2/6 signaling and reduced numbers survive birth.
Mammalian Phenotype Terms
Allelic Composition: Map3k8M1Btlr/Map3k8M1Btlr (Genetic Background: C57BL/6J-Map3k8M1Btlr )

  • mortality/aging
  • immune system
    • impaired natural killer cell mediated cytotoxicity [MP:0005070]
    • decreased interferon-alpha secretion [MP:0008563]
    • decreased interferon-beta secretion [MP:0008565]
    • decreased interleukin-1 beta secretion [MP:0008658]
    • increased interleukin-12b secretion [MP:0008669]
    • decreased interleukin-6 secretion [MP:0008706]
    • decreased tumor necrosis factor secretion [MP:0008561]
    • abnormal response to infection [MP:0005025]
  • hematopoietic system
    • impaired natural killer cell mediated cytotoxicity [MP:0005070]
Allelic Composition: Map3k8M1Btlr/Map3k8+ (Genetic Background: C57BL/6J-Map3k8M1Btlr )

  • mortality/aging
  • immune system
    • abnormal tumor necrosis factor secretion [MP:0008556]
    • decreased tumor necrosis factor secretion [MP:0008561]
MeSH Terms
  • Animals
  • Ethylnitrosourea
  • Genetic Predisposition to Disease
  • Herpesviridae Infections/genetics
  • Herpesviridae Infections/immunology
  • Interferon Type I/antagonists & inhibitors
  • Interferon Type I/biosynthesis
  • Listeriosis/genetics
  • Listeriosis/immunology
  • MAP Kinase Kinase Kinases/genetics
  • MAP Kinase Kinase Kinases/physiology
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Muromegalovirus/immunology
  • Mutagenesis/immunology
  • Proto-Oncogene Proteins/genetics
  • Proto-Oncogene Proteins/physiology
  • RNA Splicing/genetics
  • Signal Transduction/genetics
  • Signal Transduction/immunology
  • Streptococcal Infections/enzymology
  • Streptococcal Infections/genetics
  • Streptococcal Infections/immunology
  • Streptococcus agalactiae/immunology
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
  • Wildtype littermates
  • Cancer
  • Cell Biology
  • Immunology and Inflammation
Donor
Bruce Beutler, M.D., The Scripps Research Institute
Primary Reference
  • Xiao N; Eidenschenk C; Krebs P; Brandl K; Blasius AL; Xia Y; Khovananth K; Smart NG; Beutler B, The Tpl2 mutation Sluggish impairs type I IFN production and increases susceptibility to group B streptococcal disease., J Immunol 2009 Dec 15;183(12):7975-83 (Medline PMID: 19923465)
  • For additional information see: Mutagenetix, a catalog of mutations identified in the Beutler Laboratory at The Scripps Research Institute.

Colony and Husbandry Information

Colony Surveillance Program and Current Health Reports

Mice recovered from a cryo-archive will have health surveillance performed on recipient females. Health reports will be provided prior to shipment. If you require additional health status information, please email mmrrc@ucdavis.edu .

Order Request Information

Limited quantities of breeder mice (recovered litter) are available from a cryoarchive; recovered litter usually available to ship in 3 to 4 months.

Cryopreserved material may be available upon request, please inquire to mmrrc@ucdavis.edu for more information.

Distribution of this strain requires submission of the MMRRC Conditions of Use (COU). A link to the COU web form will be provided via email after an order has been placed; the form should be completed then or the email forwarded to your institutional official for completion.

The donor or their institution limits the distribution to non-profit institutions only.

Additional charges may apply for any special requests. Shipping costs are in addition to the basic distribution/resuscitation fees. Information on shipping costs and any additional charges will be provided by the supplying MMRRC facility.

Click button to Request this one strain. (Use the MMRRC Catalog Search to request more than one strain.)
MMRRC Item # Description Distribution Fee / Unit (US $) Units Notes
030499-UCD-EMBRYO Cryo-preserved embryos $1,038.00 / Non-Profit Aliquot Approximate quantity2 : 20-40 embryos / aliquot
030499-UCD-SPERM Cryo-preserved spermatozoa $546.25 / Non-Profit Aliquot Approximate quantity3
030499-UCD-RESUS Litter recovered from cryo-archive $3,033.00 / Non-Profit Litter Recovered litter4; additional fees for any special requests.

1 The distribution fee covers the expense of rederiving mice from a live mouse; 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 contains a sufficient number of embryos (in one or more vials or straws and based on the transfer success rate of the MMRRC facility) to transfer into one to three recipients. The MMRRC makes no guarantee concerning embryo transfer success experienced in the recipient investigator's laboratory. Neither gender nor genotype ratios are guaranteed.

3 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.

4 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.

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.