JAX Mouse Strain Datasheet - 006050

129-Sirt6^tm1Fwa/J

Stock No:: 006050

Targeted Mutation

Cryo Recovery

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

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Research Applications

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

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Base Price

Starting at:

$2,595.00 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):315-29. PubMed: 16439206 MGI: J:112817

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Genetics

Sirt6^tm1Fwa

Allele Symbol: Sirt6^tm1Fwa

Allele Name	targeted mutation 1, Frederick W Alt
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	SIRT6KO
Gene Symbol and Name	Sirt6, sirtuin 6
Gene Synonym(s)	2810449N18Rik; 2810449N18Rik; AI043036; RIKEN cDNA 2810449N18 gene; SIR2L6; expressed sequence 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
General Note	Phenotypic Similarity to Human Syndrome: Progeria (J:112817)
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

Research Areas By Genotype

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

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

Mammalian Phenotype Terms by Genotype

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

mortality/aging

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

integument phenotype

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

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

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

adipose tissue phenotype

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

digestive/alimentary phenotype

colitis
- consisting of erosion of the superficial colonic epithelium 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

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

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

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

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):315-29. PubMed: 16439206 MGI: J:112817

Additional - Sirt6^tm1Fwa related

Anderson JG; Ramadori G; Ioris RM; Galie M; Berglund ED; Coate KC; Fujikawa T; Pucciarelli S; Moreschini B; Amici A; Andreani C; Coppari R. 2015. Enhanced insulin sensitivity in skeletal muscle and liver by physiological overexpression of SIRT6. Mol Metab 4(11):846-56. PubMed: 26629408 MGI: J:229077
Bauer I; Grozio A; Lasiglie D; Basile G; Sturla L; Magnone M; Sociali G; Soncini D; Caffa I; Poggi A; Zoppoli G; Cea M; Feldmann G; Mostoslavsky R; Ballestrero A; Patrone F; Bruzzone S; Nencioni A. 2012. The NAD+-dependent histone deacetylase SIRT6 promotes cytokine production and migration in pancreatic cancer cells by regulating Ca2+ responses. J Biol Chem 287(49):40924-37. PubMed: 23086953 MGI: J:192629
Kawahara TL; Michishita E; Adler AS; Damian M; Berber E; Lin M; McCord RA; Ongaigui KC; Boxer LD; Chang HY; Chua KF. 2009. SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell 136(1):62-74. PubMed: 19135889 MGI: J:147591
Piao J; Tsuji K; Ochi H; Iwata M; Koga D; Okawa A; Morita S; Takeda S; Asou Y. 2013. Sirt6 regulates postnatal growth plate differentiation and proliferation via Ihh signaling. Sci Rep 3:3022. PubMed: 24149372 MGI: J:207785
Silberman DM; Ross K; Sande PH; Kubota S; Ramaswamy S; Apte RS; Mostoslavsky R. 2014. SIRT6 is required for normal retinal function. PLoS One 9(6):e98831. PubMed: 24896097 MGI: J:229652
Zhong L; D'Urso A; Toiber D; Sebastian C; Henry RE; Vadysirisack DD; Guimaraes A; Marinelli B; Wikstrom JD; Nir T; Clish CB; Vaitheesvaran B; Iliopoulos O; Kurland I; Dor Y; Weissleder R; Shirihai OS; Ellisen LW; Espinosa JM; Mostoslavsky R. 2010. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell 140(2):280-93. PubMed: 20141841 MGI: J:167957
jnlVan Meter M; Simon M; Tombline G; May A; Morello TD; Hubbard BP; Bredbenner K; Park R; Sinclair DA; Bohr VA; Gorbunova V; Seluanov A. 2016. JNK Phosphorylates SIRT6 to Stimulate DNA Double-Strand Break Repair in Response to Oxidative Stress by Recruiting PARP1 to DNA Breaks. Cell Rep 16(10):2641-50. PubMed: 27568560 MGI: J:239021

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Not-For-Profit & Academic Pricing

Service	Genotype	Price
	Please inquire about possible genotypes.

Progeny testing is not required

The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided, their gender and genotype will vary. We will fulfill your order by providing at least two pair of mice, at least one animal of each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 10 and 14 weeks from the date of your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will ship within 25 weeks.

The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory 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.

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Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

The Jackson Laboratory's Genotype Promise

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

Terms of Use

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

Phone: 207-288-6470

Email: tjlca@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

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 * 129X1/SvJ

mortality/aging

integument phenotype

cellular phenotype

growth/size/body region phenotype

adipose tissue phenotype

digestive/alimentary phenotype

hematopoietic system phenotype

homeostasis/metabolism phenotype

skeleton phenotype

immune system phenotype

References

Additional - Sirt6tm1Fwa related

Genotyping Protocols

Breeding Considerations

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

Progeny testing is not required

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 * 129X1/SvJ

Additional - Sirt6^tm1Fwa related