Overview

This mutant mouse strain contains a lacZ gene knock-in resulting in a loss of function of the targeted allele and may be useful in studies of DNA damage repair, genomic stability, and aging.

Donating Investigator

Dr. Frederick W. Alt, Children's Hospital

Genetic overview

Genetic Background	Generation

Sirt6^tm1Fwa

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Sirt6	sirtuin 6

View Genetics

Research Applications

Internal/Organ Research
Immunology, Inflammation and Autoimmunity Research
Cardiovascular Research
Cancer Research
Research Tools
Apoptosis Research
Cell Biology Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

Homozygous neonates are smaller than their wildtype and heterozygous littermates. They develop normally until approximately 21 days of age, when they develop an acute and rapid, aging-like degenerative pathology resulting in death by postnatal day 24. Homozygous mutant mice exhibit subcutaneous fat loss, lordokyphosis (hunchbacked spine) with osteopenia (30% loss of bone mineral density), colitis, and severe lymphopenia due to increased lymphocyte apoptosis. At day 12, mice have reduced insulin-like growth factor I (IGF-1) levels in serum, and develop severe hypoglycemia. Mouse embryonic fibroblasts (MEFs) prepared from homozygous embryos exhibit reduced proliferation, defective base excision repair function, as indicated by increased sensitivity to alkylating agents and ionizing radiation, and increased chromosomal aberrations. The donating investigators report that no gene product (mRNA or protein) is detected by RT-PCR or immuoblot analysis of tissues, MEFs or embryonic stem cells from homozygotes. The targeting construct placed a lacZ expression cassette in frame into exon 1 of the mRNA coding sequence, and beta-galactosidase staining is detected in most adult and embryonic tissues. This mutant mouse strain may be useful in studies related to DNA damage repair, genomic stability, and aging.

Development

A targeting vector containing the lacZ and neomycin resistance genes was used to disrupt exons 1 to 6. The construct was electroporated into 129S6/SvEvTac-derived TC1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting chimeric male animals were crossed to 129X1/SvJ female mice.

Expression Data

Expressed Gene	lacZ, beta-galactosidase, E. coli
Site of Expression	Expression of lacZ can be detected in most adult and embryonic tissues.

Control Suggestions

Wild-type from the colony

Additional Information

Considerations for Choosing Controls

Selected References

Mostoslavsky R; Chua KF; Lombard DB; Pang WW; Fischer MR; Gellon L; Liu P; Mostoslavsky G; Franco S; Murphy MM; Mills KD; Patel P; Hsu JT; Hong AL; Ford E; Cheng HL; Kennedy C; Nunez N; Bronson R; Frendewey D; Auerbach W; Valenzuela D; Karow M; Hottiger MO; Hursting S; Barrett JC; Guarente L; Mulligan R; Demple B; Yancopoulos GD; Alt FW. 2006. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124(2):315-29PubMed: 16439206 MGI: J:112817

View All References

Genetics

Sirt6^tm1Fwa

Allele Symbol: Sirt6^tm1Fwa

Allele Name	targeted mutation 1, Frederick W Alt
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	targeted mutation 1, Frederick W Alt; Sirt6^tm1Fwa
Gene Symbol and Name	Sirt6, sirtuin 6
Gene Synonym(s)	expressed sequence AI043036; SIR2L6; RIKEN cDNA 2810449N18 gene; 2810449N18Rik; 2810449N18Rik; AI043036
Expressed Gene	lacZ, beta-galactosidase, E. coli
Site of Expression	Expression of lacZ can be detected in most adult and embryonic tissues.
Strain of Origin	129S6/SvEvTac
Chromosome	10
Molecular Note	A LacZ gene was inserted in frame after the first 21 bp of exon 1 via homologous recombination replacing exons 1 to 6.

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

progeria

Research Areas By Genotype

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

Internal/Organ Research
- Lymphoid Tissue Defects
- Gastrointestinal Defects
  - colitis
Immunology, Inflammation and Autoimmunity Research
- Immunodeficiency
  - Inflammatory bowel disease
- Inflammation
  - Inflammatory bowel disease
- Lymphoid Tissue Defects
Cardiovascular Research
- Other
  - altered fat metabolism
Cancer Research
- Other
  - DNA Repair
Research Tools
- lacZ Expression
- Apoptosis Research
- Metabolism Research
- Internal/Organ Research
Apoptosis Research
- Endogenous Regulators
Cell Biology Research
- DNA Damage Response

Mammalian Phenotype Terms by Genotype

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

Genotype: Sirt6^tm1Fwa/Sirt6^tm1Fwa
involves: 129S6/SvEvTac * BALB/cJ

adipose tissue phenotype

decreased subcutaneous adipose tissue amount

mortality/aging

premature death
- 75% of females survive to age 300+ days (compared to 100% WT)
- 90% of males died before age 200 days (compared to 0% WT)

prenatal lethality, incomplete penetrance
- deviation from expected Mendelian ratio with fewer than expected transgenic mice born
- Normal - expected Mendelian ratio at age E13.5

vision/eye phenotype

abnormal cornea physiology
- inflammation at age 5-6 months

abnormal corneal stroma morphology
- edema at age 5-6 months

abnormal electroretinogram waveform feature
- reduced 16Hz flicker amplitude with photopic ERG at age 6 and 10 months

corneal scarring
- at age 5-6 months

corneal vascularization
- at age 5-6 months

decreased a wave amplitude
- with scotopic ERG at age 10 months

decreased b wave amplitude
- with scotopic ERG at age 1, 6 and 10 months

increased cornea thickness
- at age 5-6 months

retinal degeneration
- progressive age-related thinning at age 1, 6 and 10 months

thin retinal inner nuclear layer
- progressive age-related thinning at age 6 and 10 months

thin retinal outer nuclear layer
- progressive age-related thinning at age 6 and 10 months

cardiovascular system phenotype

corneal vascularization
- at age 5-6 months

growth/size/body region phenotype

decreased body weight

homeostasis/metabolism phenotype

decreased circulating insulin level
- Normal - normal basal insulin level
- significantly reduced basal insulin level

impaired glucose tolerance
- increased glucose uptake 2h after glucose injection

integument phenotype

decreased subcutaneous adipose tissue amount

mammalian phenotype

homeostasis/metabolism phenotype
- Normal - normal insulin tolerance
- Normal - normal insulin secretion after glucose stimulus

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

Genotype: Sirt6^tm1Fwa/Sirt6^tm1Fwa
involves: 129S6/SvEvTac * 129X1/SvJ

adipose tissue phenotype

decreased subcutaneous adipose tissue amount
- acute loss beginning around 3 weeks of age

hematopoietic system phenotype

abnormal B cell differentiation
- 10-fold reduction in the number of B cell progenitors in the bone marrow

abnormal lymphopoiesis
- 10-fold reduction in the number of splenic lymphoctes

decreased bone marrow cell number
- 10-fold reduction in the number of B cell progenitors in the bone marrow

decreased double-positive T cell number
- 50-fold reduction in the thymus

decreased leukocyte cell number
- adoptive transfer studies indicate increased lymphocyte apoptosis is not a cell intrinsic defect
- severe lymphopenia associated with increased lymphocyte apoptosis

spleen hypoplasia
- 10-fold reduction in the number of splenic lymphocytes

cellular phenotype

decreased cell proliferation
- in MEFs and ES cells

increased cellular sensitivity to alkylating agents
- increased sensitivity of MEFs to monofunctional alkylating agents suggesting a defect in base excision repair; however double strand break repair and nucleotide excision repair are similar to wild-type

increased cellular sensitivity to ionizing radiation
- increased DNA damage and reduced survival in MEFs and ES cells following exposure to ionizing radiation; however, UV sensitivity of MEFs is similar to wild-type cells
- thymocytes from 21 day old mice display increased sensitivity to IR and monofunctional alkylating agents; however sensitivity of cells from 12 day old mice is similar to wild-type

spontaneous chromosome breakage
- increase in the frequency of fragmented chromosome, detached centromeres and chromosomal gaps in metaphase spreads from early and late passage MEFs
- spectral karyotype analysis detects increases in the frequency of chromosome breaks, translocations, and dicentric chromosomes

homeostasis/metabolism phenotype

decreased circulating glucose level
- decreases rapidly in mice older than 12 days of age, dropping below detection limits by 24 days of age

decreased circulating insulin-like growth factor I level
- serum levels of insulin like growth factor (IGF1) are low at 12 days of age and severely by 19 days of age

immune system phenotype

abnormal B cell differentiation
- 10-fold reduction in the number of B cell progenitors in the bone marrow

abnormal lymphopoiesis
- 10-fold reduction in the number of splenic lymphoctes

colitis
- consisting of erosion of the superficial colonic epithelium beginning around 3 weeks of age

decreased double-positive T cell number
- 50-fold reduction in the thymus

decreased leukocyte cell number
- adoptive transfer studies indicate increased lymphocyte apoptosis is not a cell intrinsic defect
- severe lymphopenia associated with increased lymphocyte apoptosis

spleen hypoplasia
- 10-fold reduction in the number of splenic lymphocytes

integument phenotype

decreased subcutaneous adipose tissue amount
- acute loss beginning around 3 weeks of age

mortality/aging

lethality at weaning, complete penetrance
- fail to thrive and die around P24

skeleton phenotype

decreased bone mineral density
- 30% reduction in bone mineral density at about 3 weeks of age

kyphosis
- lordokyphosis visible around 3 weeks of age

lordosis
- lordokyphosis visible around 3 weeks of age

digestive/alimentary phenotype

colitis
- consisting of erosion of the superficial colonic epithelium beginning around 3 weeks of age

growth/size/body region phenotype

decreased body length
- decreased body length as compared to controls at 3 weeks of age on standard diet

decreased body size
- significantly smaller by about 10 days of age

decreased body weight
- decreased body weight as compared to controls at 3 weeks of age on standard diet

postnatal growth retardation
- similar size at birth but significantly smaller by about 10 days of age; however food intake is normal

References

Mostoslavsky R; Chua KF; Lombard DB; Pang WW; Fischer MR; Gellon L; Liu P; Mostoslavsky G; Franco S; Murphy MM; Mills KD; Patel P; Hsu JT; Hong AL; Ford E; Cheng HL; Kennedy C; Nunez N; Bronson R; Frendewey D; Auerbach W; Valenzuela D; Karow M; Hottiger MO; Hursting S; Barrett JC; Guarente L; Mulligan R; Demple B; Yancopoulos GD; Alt FW. 2006. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124(2):315-29PubMed: 16439206 MGI: J:112817

Additional - Sirt6^tm1Fwa related

Technical Support

Contact Technical Support

Genotyping Protocols
- Separated PCR:Sirt6^tm1Fwa
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, these mice are bred as heterozygotes. Mice homozygous for the mutation do not survive past postnatal day 24
- Additional Breeding and Husbandry Support
Citation
When using the 129-Sirt6^tm1Fwa/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #006050 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

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

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Not-For-Profit & Academic Pricing

Service	Genotype	Price
	Heterozygous or Wild-type for Sirt6<tm1Fwa>

We will fulfill your order by providing at least two carriers for each strain ordered. The total number, sex, and genotypes provided will vary, although typically 8 or more animals are provided. Please check genotypes which will be recovered. While the genotypes of all animals produced will be communicated to you prior to scheduling shipment, the genotypes of animals provided may not reflect the mating scheme and genotypes described in the strain description. Animals are typically ready to ship in 11-14 weeks. If a second recovery is required to produce the minimum number of animals, then delivery time would increase to approximately 25 weeks. If we fail to produce animals of the correct genotype, you will not be charged. We cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

Cryorecovery to establish a Dedicated Supply for greater quantities of mice. Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation.

Related Products and Services

Frozen Mouse Embryo	129-Sirt6<tm1Fwa>/J	$2595.00
Frozen Mouse Embryo	129-Sirt6<tm1Fwa>/J	$2595.00
Frozen Mouse Embryo	129-Sirt6<tm1Fwa>/J	$3373.50
Frozen Mouse Embryo	129-Sirt6<tm1Fwa>/J	$3373.50

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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.

Terms Of Use

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General Terms and Conditions

Questions about Terms of Use

Additional Use Restrictions Apply

Not Available to Companies or for Commercial Use

Strain(s) not available to companies or for-profit entities.

Licensing Information

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Email: TechTran@jax.org

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Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Expression Data

Control Suggestions

Additional Information

Selected References

Sirt6tm1Fwa

Allele Symbol: Sirt6tm1Fwa

Disease Terms

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Research Areas By Genotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Sirt6tm1Fwa/Sirt6tm1Fwainvolves: 129S6/SvEvTac * BALB/cJ

adipose tissue phenotype

mortality/aging

vision/eye phenotype

cardiovascular system phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

integument phenotype

mammalian phenotype

Genotype: Sirt6tm1Fwa/Sirt6tm1Fwainvolves: 129S6/SvEvTac * 129X1/SvJ

adipose tissue phenotype

hematopoietic system phenotype

cellular phenotype

homeostasis/metabolism phenotype

immune system phenotype

integument phenotype

mortality/aging

skeleton phenotype

digestive/alimentary phenotype

growth/size/body region phenotype

References

Additional - Sirt6tm1Fwa related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

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

Live Mouse

Cryorecovery - Not-For-Profit & Academic Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Sirt6^tm1Fwa

Allele Symbol: Sirt6^tm1Fwa

Genotype: Sirt6^tm1Fwa/Sirt6^tm1Fwa
involves: 129S6/SvEvTac * BALB/cJ

Genotype: Sirt6^tm1Fwa/Sirt6^tm1Fwa
involves: 129S6/SvEvTac * 129X1/SvJ

Additional - Sirt6^tm1Fwa related