Description

Strain Information

Type Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Mating System Heterozygote x Heterozygote         (Female x Male)   02-APR-13 Species laboratory mouse   Donating Investigator Philip C. Wong,   Johns Hopkins University

Description
These Tardbp^F mutant mice possess loxP sites flanking exon 3 of the TAR DNA binding protein gene (Tardbp; TDP-43). The Tardbp gene product, TDP-43, is a protein localized to the nucleus of nerve cells. Ubiquinated accumulations of mutant TDP-43 have been linked to the development of Lou Gehrig's disease (Amyotrophic lateral sclerosis; ALS) and frontotemporal lobar degeneration. Mice that are homozygous for this allele are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. When bred to mice that express Cre recombinase, resulting offspring will have exon 3 deleted in the cre-expressing tissues.

For example, when bred to B6;129-Gt(ROSA)26Sor^{tm1(cre/ERT)Nat}/J (Stock No. 004847), tamoxifen-induced Cre-mediated recombination results in death 9 days after induction in the offspring. These mice exhibit dramatic loss of white and brown fat due to decrease in food consumption and increased fat metabolism. These mice also display decrease in the expression of TBC1 domain family, member 1 (Tbc1d1) gene, which has been linked to leanness, human obesity, and glucose transport in skeletal muscle.

When bred to mice carrying Tg(CAG-(cre/Esr1*)5Amc (Stock No. 004682), tamoxifen-induced Cre-mediated recombination results in loss of body fat and altered fat cell morphology.

Development
A targeting vector was designed to insert a loxP site upstream of exon 3 followed by a frt-flanked neomycin resistance (neo) cassette, and a second loxP site downstream of exon 3 of the TAR DNA binding protein (Tardbp) gene. The construct was electroporated into C57BL/6-derived V26.2 embryonic stem (ES) cells, and correctly targeted ES cells were injected into B6(Cg)-Tyr^c-2J/J blastocysts. Resulting chimeric mice were bred with Bmpr1b^{Tg(ACTB-FLP)4917Dym} transgenic mice (on a B6SJL background) to delete the neo cassette, and progeny were crossed to remove the Flp-expressing transgene. Upon arrival, mice were bred to C57BL/6J inbred mice (Stock No. 000664) for at least one generation to establish the colony.

Control Information

	Control
	Wild-type from the colony
	100012 B6SJLF1/J	(approximate)
	000664 C57BL/6J	(approximate)
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Tardbp

012850

B6;129P2-TardbpGt(RRB030)Byg/J

View Strains carrying other alleles of Tardbp     (1 strain)

Additional Web Information

Use of MICE by companies or for-profit entities requires a license.

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Amyotrophic Lateral Sclerosis 10, with or without Frontotemporal Dementia;   (TARDBP)

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.
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Gt(ROSA)26Sor^{tm1(cre/ERT)Nat}/Gt(ROSA)26Sor⁺ Tardbp^tm1.1Pcw/Tardbp⁺

        involves: 129 * C57BL/6 * SJL   (conditional)

• growth/size phenotype
• decreased body weight
  • during the initial 3 days after cre induction by tamoxifen, all mice show decrease in body weight due to decreased food intake, but whereas controls regain recover some weight, experimental mice do not   (MGI Ref ID J:164406)
• homeostasis/metabolism phenotype
• abnormal respiratory quotient
  • following cre induction, animals exhibit a decreased respiratory exchange ratio (RER) indicative of pure fat oxidation compared to controls by day 6   (MGI Ref ID J:164406)
• adipose tissue phenotype
• decreased total body fat amount
  • inspection of animals dying after cre induction by tamoxifen shows loss of body fat in these mice   (MGI Ref ID J:164406)
  • analyses of carcasses show significant decreases in whole body fat mass, but not lean mass   (MGI Ref ID J:164406)

Gt(ROSA)26Sor^{tm1(cre/ERT)Nat}/Gt(ROSA)26Sor⁺ Tardbp^tm1.1Pcw/Tardbp^tm1.1Pcw

        involves: 129 * C57BL/6 * SJL   (conditional)

• mortality/aging
• abnormal survival
  • when cre expression is induced with a tamoxifen-containing diet (400 mg/kg of chow), mice die by day 9 post-introduction of tamoxifen   (MGI Ref ID J:164406)
• growth/size phenotype
• decreased body weight
  • during the initial 3 days after cre induction by tamoxifen, all mice show decrease in body weight due to decreased food intake, but whereas controls regain recover some weight, experimental mice do not   (MGI Ref ID J:164406)
• • weight loss
    • mice show a cumulative loss of body weight compared to controls following cre induction, but energy intake (cumulative food intake) is similar to controls   (MGI Ref ID J:164406)
• homeostasis/metabolism phenotype
• *normal* homeostasis/metabolism phenotype
  • without induction of cre by tamoxifen treatment, animals are indistinguishable from controls   (MGI Ref ID J:164406)
• • abnormal lipid oxidation
    • increased fat oxidation after induction is basis for increased weight loss   (MGI Ref ID J:164406)
  • abnormal respiratory quotient
    • following cre induction, animals exhibit a decreased respiratory exchange ratio (RER) indicative of pure fat oxidation compared to controls by day 6   (MGI Ref ID J:164406)
• adipose tissue phenotype
• decreased total body fat amount
  • inspection of animals dying after cre induction by tamoxifen shows loss of body fat in these mice   (MGI Ref ID J:164406)
  • analyses of carcasses show significant decreases in whole body fat mass, but not lean mass   (MGI Ref ID J:164406)
• cellular phenotype
• abnormal lipid oxidation
  • increased fat oxidation after induction is basis for increased weight loss   (MGI Ref ID J:164406)
• behavior/neurological phenotype
• abnormal food intake
  • energy intake on day 7 is significantly higher than on day 1 after cre induction   (MGI Ref ID J:164406)

Tardbp^tm1.1Pcw/Tardbp⁺ Tg(CAG-cre/Esr1*)5Amc/0

        involves: 129 * C57BL/6 * CBA * SJL   (conditional)

• growth/size phenotype
• decreased body weight
  • after cre induction by tamoxifen, mice show decrease in body weight relative to controls   (MGI Ref ID J:164406)
• adipose tissue phenotype
• abnormal brown fat cell morphology
  • absence of fatty acid vacuoles in adipocytes in interscapular brown fat is detected   (MGI Ref ID J:164406)
• abnormal white fat cell morphology
  • reduction of fatty acid vacuoles in adipocytes in subcutaneous fat is detected   (MGI Ref ID J:164406)

Tardbp^tm1.1Pcw/Tardbp^tm1.1Pcw Tg(CAG-cre/Esr1*)5Amc/0

        involves: 129 * C57BL/6 * CBA * SJL   (conditional)

• growth/size phenotype
• decreased body weight
  • after cre induction by tamoxifen, mice show decrease in body relative to controls   (MGI Ref ID J:164406)
• cellular phenotype
• abnormal lipid oxidation
  • increased fat oxidation after loss of Tardbp results in fat loss in adipocytes   (MGI Ref ID J:164406)
• adipose tissue phenotype
• abnormal brown fat cell morphology
  • absence of fatty acid vacuoles in adipocytes in interscapular brown fat is detected   (MGI Ref ID J:164406)
  • adipocytes are present in brown fat, but lack of stored fat within adipocytes results in loss of fat content in animals after induction by tamoxifen   (MGI Ref ID J:164406)
• abnormal white adipose tissue morphology   (MGI Ref ID J:164406)
• • abnormal white fat cell morphology
    • reduction of fatty acid vacuoles in adipocytes in subcutaneous fat is detected   (MGI Ref ID J:164406)
    • adipocytes are present in white fat, but lack of stored fat within adipocytes results in loss of fat content in animals after induction by tamoxifen   (MGI Ref ID J:164406)
• decreased mesenteric fat pad weight
  • dramatic fat loss is observed   (MGI Ref ID J:164406)
• decreased total body fat amount
  • inspection of animals dying after cre induction by tamoxifen shows loss of body fat in these mice   (MGI Ref ID J:164406)
  • analyses of carcasses show significant decreases in whole body fat mass, but not lean mass   (MGI Ref ID J:164406)
• homeostasis/metabolism phenotype
• abnormal lipid oxidation
  • increased fat oxidation after loss of Tardbp results in fat loss in adipocytes   (MGI Ref ID J:164406)

View Research Applications

Research Applications

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

Cardiovascular Research
Other
      altered fat metabolism

Developmental Biology Research
Postnatal Lethality
      Homozygous

Endocrine Deficiency Research
Adipose Defects

Internal/Organ Research
Adipose Defects

Neurobiology Research
Amyotrophic Lateral Sclerosis (ALS)
Cre-lox System
      loxP-flanked Sequences
Metabolic Defects

Research Tools
Cre-lox System
      loxP-flanked Sequences
Metabolism Research

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Tardbptm1.1Pcw
Allele Name		targeted mutation 1.1, Philip C Wong
Allele Type		Targeted (Floxed/Frt)
Common Name(s)		TardbpF;
Mutation Made By		Philip Wong,   Johns Hopkins University
Strain of Origin		C57BL/6
Gene Symbol and Name		Tardbp, TAR DNA binding protein
Chromosome		4
Gene Common Name(s)		1190002A23Rik; ALS10; C85084; RIKEN cDNA 1190002A23 gene; TDP-43; Tdp43; expressed sequence C85084;
Molecular Note		Exon 3 of the Tardbp gene was flanked by loxP sites. A neo cassette was inserted into exon 2. Mice carrying the mutant allele were crossed to Flp transgenic mice to delete the neo cassette. [MGI Ref ID J:164406]

Genotyping

Genotyping Information

Genotyping Protocols

Tardbp^tm1.1Pcw, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Chiang PM; Ling J; Jeong YH; Price DL; Aja SM; Wong PC. 2010. Deletion of TDP-43 down-regulates Tbc1d1, a gene linked to obesity, and alters body fat metabolism. Proc Natl Acad Sci U S A 107(37):16320-4. [PubMed: 20660762]  [MGI Ref ID J:164406]

Additional References

Tardbp^tm1.1Pcw related

Shan X; Chiang PM; Price DL; Wong PC. 2010. Altered distributions of Gemini of coiled bodies and mitochondria in motor neurons of TDP-43 transgenic mice. Proc Natl Acad Sci U S A 107(37):16325-30. [PubMed: 20736350]  [MGI Ref ID J:164382]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, homozygous mice may be bred together.
Mating System	Heterozygote x Heterozygote         (Female x Male)   02-APR-13

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

 

This strain is currently Under Development - Now Accepting Orders.
Estimated Available for Distribution Date: 29-JUL-13

Please note: You may now place orders for this strain although it is not yet ready for distribution. Estimated available for distribution dates are provided to keep customers better informed on strains under development. Please note that our Colony Managers routinely monitor the target date and edit it based on breeding performance and other factors. The length of time it takes to make a new strain available for distribution depends on genotype, age, number of animals sent by the Donating Investigator, breeding performance, additional strain development (backcrossing, making homozygous), and anticipated demand for the strain.

Control Information

	Control
	Wild-type from the colony
	100012 B6SJLF1/J	(approximate)
	000664 C57BL/6J	(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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