Overview

Also Known As:Nrf2 KO, NRF2-, Nrf2^-

Nfe2l2^tm1Ywk (NRF2) knockout mice may be useful for studying oxidative stress in the pathogenesis of age-related macular degeneration, diabetes, Parkinson's disease, and other inflammatory degenerative diseases as well as studies of cancer, multiple sclerosis, liver cirrhosis, atherosclerosis, injury and wound healing, and more.

Donating Investigator

Michael L. Freeman, Vanderbilt University

Genetic overview

Genetic Background	Generation
	N10pN1+N1F13 (2020-08-07 00:00:00)

Nfe2l2^tm1Ywk

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Nfe2l2	nuclear factor, erythroid derived 2, like 2

View Genetics

Research Applications

Research Tools
Immunology, Inflammation and Autoimmunity Research
Diabetes and Obesity Research
Sensorineural Research
Mouse/Human Gene Homologs
Neurobiology Research
Cancer Research
Cardiovascular Research

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Base Price

Starting at:

$236.78 Domestic price for female 5-week

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Details

Detailed Description

In this NRF2 knockout strain, a β-galactosidase (lacZ) reporter followed by a neomycin resistance (neo) cassette replaces exon 5 and part of exon 4 encoding the nuclear factor, erythroid derived 2, like 2 gene (Nfe2l2) gene, abolishing gene function. Homozygotes are viable, fertile, and normal in size. NRF2, a member of the "cap 'n' collar" (CNC) subfamily of the basic region-leucine zipper transcription factors, is a regulator of endogenous antioxidant protection, microglial function, and chronic neuroinflammation. Inactivation of the CNC, DNA binding, and leucine zipper domains in Nrf2^-/- mice results in age-related macular degeneration (AMD)-like retinal pathology, spontaneous choroidal neovascularization (CNV), increased sensitivity to toxins, impaired adipogenesis, abnormal mitochondria, and an increase in proinflammatory gene expression in microglia and astrocytes. The donating investigator reports that lacZ failed to generate any detectable β-galactosidase activity.

Development

A targeting vector was designed to replace exon 5 and part of exon 4 encoding the nuclear factor, erythroid derived 2, like 2 (Nfe2l2) gene with a β-galactosidase (lacZ) reporter followed by a neomycin resistance (neo) cassette and a polyadenylation sequence. The construct was electroporated into 129X1/SvJ-derived JM-1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts and the resulting chimeric mice were bred to C57BL/6 mice to generate a colony of Nrf2^-/- mice. The donating investigator reported that these mice were backcrossed to C57BL/6J (see SNP note below) for at least 10 generations . Upon arrival at The Jackson Laboratory, mice were bred to C57BL/6J (Stock No. 000664) for at least one generation.

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 1 of the 27 markers throughout the genome was segregating for 129, suggested a C57BL/6 genetic background, 4 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 Suggestions

Approximate Controls

000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Chan K; Lu R; Chang JC; Kan YW. 1996. NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development. Proc Natl Acad Sci U S A 93(24):13943-8PubMed: 8943040 MGI: J:37053

View All References

Genetics

Nfe2l2^tm1Ywk

Allele Symbol: Nfe2l2^tm1Ywk

Allele Name	targeted mutation 1, Yuet Wai Kan
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	NRF2-; Nrf2 KO
Gene Symbol and Name	Nfe2l2, nuclear factor, erythroid derived 2, like 2
Gene Synonym(s)
Strain of Origin	129X1/SvJ
Chromosome	2
Molecular Note	A 4.2 kb segment, includind part of exon 4 and all of exon 5, was replaced by an in-frame lacZ gene followed by a neomycin selection cassette. Northern blot analysis on RNA derived from various tissues confirmed that a fusion transcript was detectable in intestine of homozygous mice, but no wild-type transcript was detectable in any tissue. However, no fusion protein was detected by histochemical staining in any adult tissue.
Mutations Made By	Yuet Wai Kan, University of California SF

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

Research Tools
- Toxicology Research
  - free radical research
Immunology, Inflammation and Autoimmunity Research
Diabetes and Obesity Research
Sensorineural Research
- Retinal Degeneration
Mouse/Human Gene Homologs
- retinal degeneration, slow
Neurobiology Research
- Parkinson's Disease
  - increased vulnerability to MPTP
Cancer Research
- Other
Cardiovascular Research
- Atherosclerosis
Internal/Organ Research
- Wound Healing

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Nfe2l2^tm1Ywk/Nfe2l2^tm1Ywk
involves: 129X1/SvJ

cellular phenotype

decreased hepatocyte proliferation
- during regeneration following partial hepatectomy

increased cellular sensitivity to hydrogen peroxide
- in splenocytes and erythrocytes

increased fibroblast apoptosis
- primary fibroblasts exhibit a small increase in apoptosis compared to wild-type cells

increased splenocyte apoptosis

oxidative stress
- cultured fibroblasts exhibit a 2-fold increase in oxidative stress compared to wild-type cells
- hydrogen peroxide-treated erythrocytes exhibit increased IgG binding compared to similarly treated wild-type cells
- myelin sheaths accumulate evidence of oxidant injury unlike in wild-type mice
- oxidative stress in primary hepatocytes is increased compared to in wild-type cells

craniofacial phenotype

abnormal tooth morphology
- teeth are white unlike in wild-type mice

growth/size/body region phenotype

abnormal tooth morphology
- teeth are white unlike in wild-type mice

enlarged spleen

increased spleen weight
- 9.1-fold

hematopoietic system phenotype

abnormal erythrocyte physiology
- erythrocytes exhibit increased levels of IgG and IgM due to increased levels of oxidative damage compared to wild-type cells
- erythrocytes exhibit increased methemoglobin formation after incubation with high concentration of hydrogen peroxide unlike similarly treated wild-type cells
- erythrocytes exhibit increased sensitivity to hydrogen peroxide-induced cytotoxicity compared to similarly treated wild-type cell
- hydrogen peroxide-treated erythrocytes exhibit increased IgG binding compared to similarly treated wild-type cells

abnormal splenocyte physiology
- splenocytes exhibit increased sensitivity to hydrogen peroxide-induced cytotoxicity compared to wild-type cells

acanthocytosis

anisocytosis
- mild at 6 months of age

decreased erythrocyte cell number

decreased hematocrit

decreased hemoglobin content

enlarged spleen

hemolytic anemia
- mice exhibit hemolytic anemia at 6 months that is more severe in older mice

increased macrophage cell number
- at day 13 post-wound unlike in wild-type mice

increased number of Howell-Jolly bodies

increased spleen weight
- 9.1-fold

increased splenocyte apoptosis

poikilocytosis
- mild at 6 months of age

reticulocytosis
- due to increased production

schistocytosis

thrombocytopenia

homeostasis/metabolism phenotype

decreased circulating interleukin-1 beta level
- by 30% in mice with 1 day old wounds compared to similarly treated wild-type mice

increased circulating bilirubin level

increased circulating interleukin-1 beta level
- at day 13 post-wound, mice exhibit a 4-fold higher level of plasma IL-1b compared to similarly treated wild-type mice
- by 60% in mice with 5 day old wounds compared to similarly treated wild-type mice

increased lactate dehydrogenase level
- following incubation of erythrocytes in hydrogen peroxide

immune system phenotype

abnormal spleen physiology
- spleen inflammation

abnormal splenocyte physiology
- splenocytes exhibit increased sensitivity to hydrogen peroxide-induced cytotoxicity compared to wild-type cells

decreased circulating interleukin-1 beta level
- by 30% in mice with 1 day old wounds compared to similarly treated wild-type mice

enlarged spleen

increased circulating interleukin-1 beta level
- at day 13 post-wound, mice exhibit a 4-fold higher level of plasma IL-1b compared to similarly treated wild-type mice
- by 60% in mice with 5 day old wounds compared to similarly treated wild-type mice

increased macrophage cell number
- at day 13 post-wound unlike in wild-type mice

increased spleen weight
- 9.1-fold

increased splenocyte apoptosis

liver/biliary system phenotype

abnormal liver physiology
- during regeneration following partial hepatectomy, hepatocyte apoptosis rates are increased 5-fold compared to in similarly treated wild-type mice
- oxidative stress in primary hepatocytes is increased compared to in wild-type cells

decreased hepatocyte proliferation
- during regeneration following partial hepatectomy

decreased liver regeneration
- delayed

decreased liver weight

mammalian phenotype

embryo phenotype
- Normal - mice develop normally at E13.5 and E15.5

hematopoietic system phenotype
- Normal - at 6 weeks of age, all hematological indices are within normal ranges

homeostasis/metabolism phenotype
- Normal - the rate of wound is normal

nervous system phenotype

abnormal myelin sheath morphology
- mice exhibit multiloculated cystic dilation and whorls of myelin unlike wild-type mice
- myelin sheaths accumulate evidence of oxidant injury unlike in wild-type mice

astrocytosis
- in the absence of neurodegeneration

spongiform encephalopathy
- 54% of mice develop vacuolar leukoencephalopathy at a mean age of 8 months wild-type mice
- by 1 year of age, all mice exhibit vacuolar leukoencephalopathy affecting all areas of the brain and prominently in the cerebellar and pontine white tracts
- Normal - however, neurodegeneration is not observed

skeleton phenotype

abnormal tooth morphology
- teeth are white unlike in wild-type mice

Genotype: Nfe2l2^tm1Ywk/Nfe2l2^tm1Ywk
involves: 129X1/SvJ * C57BL

cardiovascular system phenotype

lung hemorrhage
- lungs of BHT-treated mice are hemorrhagic unlike in similarly treated wild-type mice

growth/size/body region phenotype

enlarged lung
- lungs of BHT-treated mice are enlarged unlike in similarly treated wild-type mice

homeostasis/metabolism phenotype

increased physiological sensitivity to xenobiotic
- lungs of BHT-treated mice are enlarged and hemorrhagic with pulmonary infiltrates and destruction of alveolar structure unlike in similarly treated wild-type mice
- mice treated with BHT (BHA and butylated hydroxytoluene) exhibit increased lung injury and mortality compared to similarly treated wild-type mice

increased sensitivity to xenobiotic induced morbidity/mortality
- mice treated with 0.5% and 0.1% BHT (BHA and butylated hydroxytoluene) exhibit 59% and 80% mortality, respectively, unlike similarly treated wild-type mice that do not die

mortality/aging

increased sensitivity to xenobiotic induced morbidity/mortality
- mice treated with 0.5% and 0.1% BHT (BHA and butylated hydroxytoluene) exhibit 59% and 80% mortality, respectively, unlike similarly treated wild-type mice that do not die

respiratory system phenotype

enlarged lung
- lungs of BHT-treated mice are enlarged unlike in similarly treated wild-type mice

lung hemorrhage
- lungs of BHT-treated mice are hemorrhagic unlike in similarly treated wild-type mice

The following phenotype relates to a compound genotype created using this strain

Genotype: Nfe2l2^tm1Ywk/Nfe2l2^tm1Ywk
B6.129X1-Nfe2l2/J

cellular phenotype

oxidative stress
- analysis of 8-OHdG+ cell levels in different regions revealed significant ROS-mediated damage in the epithelium and connective tissue relative to bone
- in a ligature-induced periodontitis model, mutant mice exhibit significantly higher levels of 8-hydroxydeoxyguanosine (8-OHdG) around ligated molars than wild-type controls, indicating high oxidative damage at sites with periodontitis

homeostasis/metabolism phenotype

decreased catalase level
- mutant bone marrow (BM) polymorphonuclear neutrophils (PMNs) produce significantly lower catalase levels than wild-type BM-PMNs

immune system phenotype

abnormal neutrophil physiology
- mutant BM-PMNs exhibit a higher migration speed along an formylmethionine-leucyl-phenylalanine gradient than wild-type BM-PMNs; however, overall migration efficiency (% migrated cells) is normal
- mutant BM-PMNs produce significantly lower catalase levels than wild-type BM-PMNs
- Normal - mutant BM-PMNs show normal extracellular reactive oxygen species (ROS) production in response to phorbolmyristate acetate stimulation

skeleton phenotype

abnormal periodontal ligament morphology
- in a ligature-induced periodontitis model, mutant mice display significantly more epithelial and connective tissue attachment loss than wild-type controls, indicating increased periodontal tissue breakdown at sites with periodontitis

alveolar process atrophy
- in a ligature-induced periodontitis model, mutant mice display significantly more alveolar bone loss at sites with periodontitis relative to wild-type controls

craniofacial phenotype

abnormal periodontal ligament morphology
- in a ligature-induced periodontitis model, mutant mice display significantly more epithelial and connective tissue attachment loss than wild-type controls, indicating increased periodontal tissue breakdown at sites with periodontitis

alveolar process atrophy
- in a ligature-induced periodontitis model, mutant mice display significantly more alveolar bone loss at sites with periodontitis relative to wild-type controls

growth/size/body region phenotype

abnormal periodontal ligament morphology
- in a ligature-induced periodontitis model, mutant mice display significantly more epithelial and connective tissue attachment loss than wild-type controls, indicating increased periodontal tissue breakdown at sites with periodontitis

alveolar process atrophy
- in a ligature-induced periodontitis model, mutant mice display significantly more alveolar bone loss at sites with periodontitis relative to wild-type controls

hematopoietic system phenotype

abnormal neutrophil physiology
- mutant BM-PMNs exhibit a higher migration speed along an formylmethionine-leucyl-phenylalanine gradient than wild-type BM-PMNs; however, overall migration efficiency (% migrated cells) is normal
- mutant BM-PMNs produce significantly lower catalase levels than wild-type BM-PMNs
- Normal - mutant BM-PMNs show normal extracellular reactive oxygen species (ROS) production in response to phorbolmyristate acetate stimulation

References

Chan K; Lu R; Chang JC; Kan YW. 1996. NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development. Proc Natl Acad Sci U S A 93(24):13943-8PubMed: 8943040 MGI: J:37053

Additional References

Sampath C; Sprouse JC; Freeman ML; Gangula PR. 2019. Activation of Nrf2 attenuates delayed gastric emptying in obesity induced diabetic (T2DM) female mice. Free Radic Biol Med 135:132-143PubMed: 30831189 MGI: J:292663
Zhou C; Luo D; Xia W; Gu C; Lahm T; Xu X; Qiu Q; Zhang Z. 2019. Nuclear Factor (Erythroid-Derived 2)-Like 2 (Nrf2) Contributes to the Neuroprotective Effects of Histone Deacetylase Inhibitors In Retinal Ischemia-Reperfusion Injury. Neuroscience 418:25-36PubMed: 31442569 MGI: J:283009

Additional - Nfe2l2^tm1Ywk related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Separated PCR:GAL Panel-B6J vs. 129S
- Standard PCR:Nfe2l2
- Standard PCR:Nfe2l2
- Separated PCR:GAL Panel-B6J vs. 129S JR 400174
- Separated PCR:GAL Panel-B6J vs. B6N
- Genotyping resources and troubleshooting
Dietary Information
- New Diet as of March 2015: Lab Diet® 5K0Q (6% fat)
Breeding Considerations

When maintaining a live colony, homozygous mice may be bred together. Our experience has been that homozygous breeders produced small litters.
- Additional Breeding and Husbandry Support
Mating System
- Homozygote x Homozygote
Appearance
- Black or Agouti*
  *contact Technical Information Services via Customer Service for details
Citation
When using the Nrf2^- mouse strain in a publication, please cite the originating article(s) and include JAX stock #017009 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

AX12 (Maximum)

Pricing & Availability

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Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Heterozygous for

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Frozen Mouse Embryo	B6.129X1-Nfe2l2<tm1Ywk>/J Frozen Embryo	$3373.50

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Also Known As:Nrf2 KO, NRF2-, Nrf2-

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Approximate Controls

Additional Information

Selected References

Nfe2l2tm1Ywk

Allele Symbol: Nfe2l2tm1Ywk

Disease Terms

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Nfe2l2tm1Ywk/Nfe2l2tm1Ywkinvolves: 129X1/SvJ

cellular phenotype

craniofacial phenotype

growth/size/body region phenotype

hematopoietic system phenotype

homeostasis/metabolism phenotype

immune system phenotype

liver/biliary system phenotype

mammalian phenotype

nervous system phenotype

skeleton phenotype

Genotype: Nfe2l2tm1Ywk/Nfe2l2tm1Ywkinvolves: 129X1/SvJ * C57BL

cardiovascular system phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

mortality/aging

respiratory system phenotype

Genotype: Nfe2l2tm1Ywk/Nfe2l2tm1YwkB6.129X1-Nfe2l2/J

cellular phenotype

homeostasis/metabolism phenotype

immune system phenotype

skeleton phenotype

craniofacial phenotype

growth/size/body region phenotype

hematopoietic system phenotype

References

Additional References

Additional - Nfe2l2tm1Ywk related

Genotyping Protocols

Dietary Information

Breeding Considerations

Mating System

Appearance

Citation

Animal Health Reports

Live Mouse

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Also Known As:Nrf2 KO, NRF2-, Nrf2^-

Nfe2l2^tm1Ywk

Allele Symbol: Nfe2l2^tm1Ywk

Genotype: Nfe2l2^tm1Ywk/Nfe2l2^tm1Ywk
involves: 129X1/SvJ

Genotype: Nfe2l2^tm1Ywk/Nfe2l2^tm1Ywk
involves: 129X1/SvJ * C57BL

Genotype: Nfe2l2^tm1Ywk/Nfe2l2^tm1Ywk
B6.129X1-Nfe2l2/J

Additional - Nfe2l2^tm1Ywk related