Strain Name:

B6.129-Nlrp3tm1Hhf/J

Stock Number:

017969

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Availability:

Repository- Live

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These knock-in mice contain a floxed neomycin cassette (neoR) in opposite orientation to a mutated Nlrp3 gene resembling the human mutation associated with Muckle-Wells syndrome. When bred to mice that express Cre recombinase to delete the floxed-neoR, the mutant gene is expressed in cre-expressing tissues of the offspring. These mice may be useful in studying the role of cryopyrin in the regulation of autoinflammatory diseases.

Description

Strain Information

Former Names B6N.129-Nlrp3tm1Hhf/J    (Changed: 20-DEC-12 )
Type Congenic; Mutant Strain; Targeted Mutation;
Additional information on Genetically Engineered and Mutant Mice.
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Mating SystemHomozygote x Homozygote         (Female x Male)   16-JAN-13
Specieslaboratory mouse
GenerationN10+N1f5 (18-JUL-12)
Generation Definitions
 
Donating Investigator Hal M Hoffman,   UCSD

Description
Nlrp3A350VneoR mice contain a floxed neomycin cassette in intron 2 of the NLR family, pyrin domain containing 3 gene, Nlrp3, in opposite orientation to gene (neoR). These mice also contain a point mutation in exon 3 which results in a missense mutation, A350V, corresponding to human amino acid 352. This mutation is commonly found in humans with Muckle-Wells syndrome (MWS). NLRP3 encodes the protein cryopyrin, which is a cytosolic nucleotide-binding domain and leucine-rich repeat containing (NLR) protein expressed in white blood cells and chondrocytes. Cryopyrin controls the formation of the inflammasome which regulates the immune system's response to injury, toxins, and infection by cleaving interleukin (IL)-1β. NLRP3 mutations are known to cause autoinflammatory diseases known as cryopyrin-associated periodic syndromes (CAPS) such as MWS, familial cold autoinflammatory syndrome (FCAS), and neonatal onset multisystem inflammatory disease (NOMID). Homozygotes are viable and fertile. When bred to mice that express Cre recombinase, resulting offspring will have the floxed-neoR deleted in the cre-expressing tissues, allowing expression of the mutant gene.

For example, when bred to B6.129P2-Lyz2tm1(cre)Ifo/J mice (Stock No. 004781), Nlrp3A350VneoR expression in myeloid lineage cells results in postnatal lethality, with 70% of mice dying by 14 days of age. Neutrophilic infiltrates are evident in skin, liver, spleen, joint, sinus, conjunctiva, bone marrow, and tongue. They lack hair and have red scaly skin, and exhibit extreme necrosis of the gut and kidney.

When bred to mice carrying Tg(CAG-(cre/Esr1*)5Amc (Stock No. 004682), tamoxifen-induced Cre-mediated recombination results in hypersecretion of IL1b and an enhanced ability to stimulation T cell differentiation by activated dendritic cells.

When bred to mice carrying Tg(Zp3-cre)3Mrt (Stock No. 003394), Cre recombinase expression in the oocyte results in postnatal lethality from multi-organ failure following inflammation and necrosis.

Development
A targeting vector was designed to insert a loxP-flanked neomycin resistance (neo) cassette, in reverse orientation to the gene, into intron 2 of the NLR family, pyrin domain containing 3 gene, Nlrp3. A point mutation was introduced into exon 3,resulting in a missense mutation, A350V, corresponding to human amino acid 352. This mutation is commonly found in humans with cryopyrin-associated periodic syndromes (CAPS). The construct was electroporated into 129/SvJ-derived embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts and chimeric mice were bred to C57BL/6NCrl mice. The donating investigator reports that mutant mice were backcrossed to C57BL/6NCrl for at least ten generations (see SNP note below) prior to sending to The Jackson Laboratory. Upon arrival, heterozygous sperm was frozen. To generate the live colony, an aliquot of the frozen sperm was used to fertilize oocytes from C57BL/6NJ inbred females (Stock No. 005304).

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, all 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 C57BL/6J genetic background.

Control Information

  Control
   000664 C57BL/6J (approximate)
   005304 C57BL/6NJ (approximate)
 
  Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Nlrp3
021302   B6.129S6-Nlrp3tm1Bhk/J
017970   B6N.129-Nlrp3tm2Hhf/J
017971   B6N.129-Nlrp3tm3Hhf/J
View Strains carrying other alleles of Nlrp3     (3 strains)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI
- Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).
Muckle-Wells Syndrome; MWS
- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested.
CINCA Syndrome; CINCA   (NLRP3)
Familial Cold Autoinflammatory Syndrome 1; FCAS1   (NLRP3)
View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI
      assigned by genotype

The following phenotype relates to a compound genotype created using this strain.
Contact JAX® Services jaxservices@jax.org for customized breeding options.

Nlrp3tm1Flv/Nlrp3tm1Hhf Lyz2tm1(cre)Ifo/Lyz2+

        involves: 129 * C57BL/6   (conditional)
  • mortality/aging
  • complete postnatal lethality
    • mice die between 2 and 14 days after birth probably due to multisystem organ failure secondary to inflammation and necrosis   (MGI Ref ID J:150054)
    • genotype demonstrates inflammatory disease of the conditional allele does not require presence of wild-type allele   (MGI Ref ID J:150054)
  • immune system phenotype
  • increased inflammatory response
    • mice have pronounced leukocytic infiltrates in skin, liver, spleen, joint, sinus, conjunctiva, bone marrow, and tongue that are mainly neutrophilic   (MGI Ref ID J:150054)

Nlrp3tm1Hhf/Nlrp3+ Lyz2tm1(cre)Ifo/Lyz2+

        involves: 129/Sv * 129P2/OlaHsd * C57BL/6   (conditional)
  • mortality/aging
  • complete postnatal lethality
    • mice die between 2 and 14 days after birth probably due to multisystem organ failure secondary to inflammation and necrosis   (MGI Ref ID J:150054)
    • 70% of mice die between 7-14 days   (MGI Ref ID J:150054)
  • growth/size/body phenotype
  • slow postnatal weight gain
    • mutant pups gained weight slowly, and then lost weight before dying   (MGI Ref ID J:150054)
  • digestive/alimentary phenotype
  • abnormal intestine morphology
    • substantial necrosis occurs in the gut that is not associated with inflammation   (MGI Ref ID J:150054)
  • renal/urinary system phenotype
  • abnormal kidney morphology
    • substantial necrosis occurs in the kidney that is not associated with inflammation   (MGI Ref ID J:150054)
  • immune system phenotype
  • abnormal circulating cytokine level
    • GCSF is elevated in the sera of 6-8 day old mice   (MGI Ref ID J:150054)
    • abnormal circulating chemokine level
      • CXCL1 levels are elevated in the sera of mice 6-8 days old   (MGI Ref ID J:150054)
    • increased circulating interleukin-1 beta level
      • IL-1beta levels in the sera of 6-8 day old mice are elevated 3-fold   (MGI Ref ID J:150054)
      • levels of this cytokine are also elevated in the dermis and epidermis, which may contribute to the skin pathology   (MGI Ref ID J:150054)
    • increased circulating interleukin-18 level
      • IL-18 levels are elevated in the sera of 6-8 day old mice   (MGI Ref ID J:150054)
    • increased circulating interleukin-6 level
      • IL-6 levels are elevated in the sera of 6-8 day old mice   (MGI Ref ID J:150054)
      • levels of this cytokine are also elevated in the dermis and epidermis, which may contribute to the skin pathology   (MGI Ref ID J:150054)
    • increased circulating tumor necrosis factor level
      • TNF levels in the sera of 6-8 day old mice are elevated   (MGI Ref ID J:150054)
  • increased inflammatory response
    • mice have pronounced leukocytic infiltrates in skin, liver, spleen, joint, sinus, conjunctiva, bone marrow, and tongue that are mainly neutrophilic   (MGI Ref ID J:150054)
  • increased leukocyte cell number
    • white blood cell count is mildly elevated   (MGI Ref ID J:150054)
    • increased neutrophil cell number
      • pronounced neutrophilia is evident in these mice   (MGI Ref ID J:150054)
  • homeostasis/metabolism phenotype
  • abnormal circulating cytokine level
    • GCSF is elevated in the sera of 6-8 day old mice   (MGI Ref ID J:150054)
    • abnormal circulating chemokine level
      • CXCL1 levels are elevated in the sera of mice 6-8 days old   (MGI Ref ID J:150054)
    • increased circulating interleukin-1 beta level
      • IL-1beta levels in the sera of 6-8 day old mice are elevated 3-fold   (MGI Ref ID J:150054)
      • levels of this cytokine are also elevated in the dermis and epidermis, which may contribute to the skin pathology   (MGI Ref ID J:150054)
    • increased circulating interleukin-18 level
      • IL-18 levels are elevated in the sera of 6-8 day old mice   (MGI Ref ID J:150054)
    • increased circulating interleukin-6 level
      • IL-6 levels are elevated in the sera of 6-8 day old mice   (MGI Ref ID J:150054)
      • levels of this cytokine are also elevated in the dermis and epidermis, which may contribute to the skin pathology   (MGI Ref ID J:150054)
    • increased circulating tumor necrosis factor level
      • TNF levels in the sera of 6-8 day old mice are elevated   (MGI Ref ID J:150054)
  • hematopoietic system phenotype
  • increased leukocyte cell number
    • white blood cell count is mildly elevated   (MGI Ref ID J:150054)
    • increased neutrophil cell number
      • pronounced neutrophilia is evident in these mice   (MGI Ref ID J:150054)
  • increased platelet cell number
    • thrombocytosis is evident in these mice   (MGI Ref ID J:150054)
  • integument phenotype
  • hairless
    • hair growth does not occur in these mice   (MGI Ref ID J:150054)
  • reddish skin
    • 1-2 day old mice have skin abscesses that develop into erythema and scaly skin by day 4   (MGI Ref ID J:150054)
  • scaly skin
    • 1-2 day old mice have skin abscesses that develop into erythema and scaly skin by day 4   (MGI Ref ID J:150054)

Nlrp3tm1Hhf/Nlrp3+ Tg(CAG-cre/Esr1*)5Amc/?

        involves: 129/Sv * C57BL/6 * CBA
  • growth/size/body phenotype
  • slow postnatal weight gain
    • some older mice have slower weight gain   (MGI Ref ID J:150054)
  • immune system phenotype
  • skin inflammation
    • some older mice develop skin inflammation suggesting leaky expression of the cre recombinase   (MGI Ref ID J:150054)
  • integument phenotype
  • skin inflammation
    • some older mice develop skin inflammation suggesting leaky expression of the cre recombinase   (MGI Ref ID J:150054)

Nlrp3tm1Hhf/Nlrp3+ Tg(CAG-cre/Esr1*)5Amc/?

        involves: 129/Sv * C57BL/6 * CBA   (conditional)
  • immune system phenotype
  • abnormal dendritic cell physiology
    • bone marrow derived dendritic cells hypersecrete the mature form of IL-1beta in response to activation   (MGI Ref ID J:150054)
    • the maximal response is 300-fold greater than controls   (MGI Ref ID J:150054)
    • DCs are able to secrete IL1-beta without the presence of exogenous ATP   (MGI Ref ID J:150054)
    • abnormal dendritic cell antigen presentation
      • mutant DCs cells have an enhanced ability to stimulate T cells to differentiate into a Th17 subtypes when presenting cognate antigen   (MGI Ref ID J:150054)
      • mutant DCs also enhance Th1 and Th2 differentation when co-cultured with T cells in the presence of polarizing cytokines   (MGI Ref ID J:150054)
  • abnormal macrophage physiology
    • peritoneal macrophages are able to secrete IL-1beta in the absence of ATP when activated in vitro   (MGI Ref ID J:150054)
  • hematopoietic system phenotype
  • abnormal macrophage physiology
    • peritoneal macrophages are able to secrete IL-1beta in the absence of ATP when activated in vitro   (MGI Ref ID J:150054)

Nlrp3tm1Hhf/Nlrp3+ Tg(Zp3-cre)3Mrt/?

        involves: 129/Sv * FVB/N   (conditional)
  • mortality/aging
  • complete postnatal lethality
    • mice die between 2 and 14 days after birth probably due to multisystem organ failure secondary to inflammation and necrosis   (MGI Ref ID J:150054)
  • growth/size/body phenotype
  • slow postnatal weight gain
    • mutant pups gained weight slowly, and then lost weight before dying   (MGI Ref ID J:150054)
  • immune system phenotype
  • increased inflammatory response
    • mice have pronounced leukocytic infiltrates in skin, liver, spleen, joint, sinus, conjunctiva, bone marrow, and tongue that are mainly neutrophilic   (MGI Ref ID J:150054)
  • increased leukocyte cell number
    • white blood cell count is mildly elevated   (MGI Ref ID J:150054)
    • increased neutrophil cell number
      • pronounced neutrophilia is evident in these mice   (MGI Ref ID J:150054)
  • digestive/alimentary phenotype
  • abnormal intestine morphology
    • substantial necrosis occurs in the gut that is not associated with inflammation   (MGI Ref ID J:150054)
  • renal/urinary system phenotype
  • abnormal kidney morphology
    • substantial necrosis occurs in the kidney that is not associated with inflammation   (MGI Ref ID J:150054)
  • hematopoietic system phenotype
  • increased leukocyte cell number
    • white blood cell count is mildly elevated   (MGI Ref ID J:150054)
    • increased neutrophil cell number
      • pronounced neutrophilia is evident in these mice   (MGI Ref ID J:150054)
  • increased platelet cell number
    • thrombocytosis is evident in these mice   (MGI Ref ID J:150054)
  • integument phenotype
  • hairless
    • hair growth does not occur in these mice   (MGI Ref ID J:150054)
  • reddish skin
    • 1-2 day old mice have skin abscesses that develop into erythema and scaly skin by day 4   (MGI Ref ID J:150054)
  • scaly skin
    • 1-2 day old mice have skin abscesses that develop into erythema and scaly skin by day 4   (MGI Ref ID J:150054)
View Research Applications

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

Immunology, Inflammation and Autoimmunity Research
Inflammation

Research Tools
Cre-lox System
      loxP-flanked Sequences

Genes & Alleles

Gene & Allele Information provided by MGI

 
Allele Symbol Nlrp3tm1Hhf
Allele Name targeted mutation 1, Hal M Hoffman
Allele Type Targeted (knock-in)
Common Name(s) Nlrp3A350VneoR;
Mutation Made By Hal Hoffman,   UCSD
Strain of Origin129/Sv
Promoter Nlrp3, NLR family, pyrin domain containing 3, mouse, laboratory
Molecular Note The alanine 352 to valine human mutation associated with Muckle-Wells syndrome was produced in mice by changing the equivalent alanine at position 350 to a valine (A350V). A floxed neomycin cassette was inserted in the reverse orientation into intron 2,which is upstream of the point mutation in exon 3. Sequence analysis of transcripts isolated from heterozygote mice demonstrate the mutant allele is not expressed due to the presence of the neomycin cassette. In the presence of cre recombinase, the neomycin cassette is removed and the mutant allele is expressed. [MGI Ref ID J:150054]

Genotyping

Genotyping Information

Genotyping Protocols

** Nlrp3*A350V, Pyrosequencing
Nlrp3tm#HhfMCA,

Separated MCA


Nlrp3tm#Hhf, Separated PCR


Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Brydges SD; Mueller JL; McGeough MD; Pena CA; Misaghi A; Gandhi C; Putnam CD; Boyle DL; Firestein GS; Horner AA; Soroosh P; Watford WT; O'Shea JJ; Kastner DL; Hoffman HM. 2009. Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity. Immunity 30(6):875-87. [PubMed: 19501000]  [MGI Ref ID J:150054]

Additional References

Nlrp3tm1Hhf related

Brydges SD; Broderick L; McGeough MD; Pena CA; Mueller JL; Hoffman HM. 2013. Divergence of IL-1, IL-18, and cell death in NLRP3 inflammasomopathies. J Clin Invest :. [PubMed: 24084736]  [MGI Ref ID J:203992]

Henao-Mejia J; Elinav E; Jin C; Hao L; Mehal WZ; Strowig T; Thaiss CA; Kau AL; Eisenbarth SC; Jurczak MJ; Camporez JP; Shulman GI; Gordon JI; Hoffman HM; Flavell RA. 2012. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482(7384):179-85. [PubMed: 22297845]  [MGI Ref ID J:181354]

McGeough MD; Pena CA; Mueller JL; Pociask DA; Broderick L; Hoffman HM; Brydges SD. 2012. Cutting edge: IL-6 is a marker of inflammation with no direct role in inflammasome-mediated mouse models. J Immunol 189(6):2707-11. [PubMed: 22904305]  [MGI Ref ID J:189914]

Norton JT; Hayashi T; Crain B; Cho JS; Miller LS; Corr M; Carson DA. 2012. Cutting edge: nitrogen bisphosphonate-induced inflammation is dependent upon mast cells and IL-1. J Immunol 188(7):2977-80. [PubMed: 22387558]  [MGI Ref ID J:183090]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX18

Colony Maintenance

Breeding & HusbandryWhen maintaining a live colony, homozygous mice may be bred together.
Mating SystemHomozygote x Homozygote         (Female x Male)   16-JAN-13
Diet Information LabDiet® 5K20

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls


Pricing for USA, Canada and Mexico shipping destinations View International Pricing

Live Mice

Price per mouse (US dollars $)GenderGenotypes Provided
Individual Mouse $232.00Female or MaleHomozygous for Nlrp3tm1Hhf  
Price per Pair (US dollars $)Pair Genotype
$464.00Homozygous for Nlrp3tm1Hhf x Homozygous for Nlrp3tm1Hhf  

Standard Supply

Repository-Live.
Repository-Live represents an exclusive set of over 1500 unique mouse models across a vast array of research areas. Breeding colonies provide mice for both large and small orders and fluctuate in size depending on current demand for each strain. If a Repository strain is not immediately available, then within 2 to 3 business days, you will receive an estimated availability timeframe for your inquiry or order along with various delivery options. Repository strains typically are delivered at 4 to 8 weeks of age and will not exceed 12 weeks of age on the day of shipping. We will note and try to accommodate requests for specific ages of Repository strains but cannot guarantee provision of these strains at specific ages. However, if cohorts of mice (5 or more of one gender) are needed at a specific age range for experiments, please let us know.

Pricing for International shipping destinations View USA Canada and Mexico Pricing

Live Mice

Price per mouse (US dollars $)GenderGenotypes Provided
Individual Mouse $301.60Female or MaleHomozygous for Nlrp3tm1Hhf  
Price per Pair (US dollars $)Pair Genotype
$603.20Homozygous for Nlrp3tm1Hhf x Homozygous for Nlrp3tm1Hhf  

Standard Supply

Repository-Live.
Repository-Live represents an exclusive set of over 1500 unique mouse models across a vast array of research areas. Breeding colonies provide mice for both large and small orders and fluctuate in size depending on current demand for each strain. If a Repository strain is not immediately available, then within 2 to 3 business days, you will receive an estimated availability timeframe for your inquiry or order along with various delivery options. Repository strains typically are delivered at 4 to 8 weeks of age and will not exceed 12 weeks of age on the day of shipping. We will note and try to accommodate requests for specific ages of Repository strains but cannot guarantee provision of these strains at specific ages. However, if cohorts of mice (5 or more of one gender) are needed at a specific age range for experiments, please let us know.

View USA Canada and Mexico Pricing View International Pricing

Standard Supply

Repository-Live.
Repository-Live represents an exclusive set of over 1500 unique mouse models across a vast array of research areas. Breeding colonies provide mice for both large and small orders and fluctuate in size depending on current demand for each strain. If a Repository strain is not immediately available, then within 2 to 3 business days, you will receive an estimated availability timeframe for your inquiry or order along with various delivery options. Repository strains typically are delivered at 4 to 8 weeks of age and will not exceed 12 weeks of age on the day of shipping. We will note and try to accommodate requests for specific ages of Repository strains but cannot guarantee provision of these strains at specific ages. However, if cohorts of mice (5 or more of one gender) are needed at a specific age range for experiments, please let us know.

Control Information

  Control
   000664 C57BL/6J (approximate)
   005304 C57BL/6NJ (approximate)
 
  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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