Description

Strain Information

Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse   Donating Investigator Yaacov Barak,   The Jackson Laboratory

Description
These mice express tTA (tetracycline regulated transactivator) and a tetO-driven Flag-tagged Pparg from the endogenous Pparg locus. A fusion transcript (including the 5' portion of Pparg, IRES and tTA (AF1-IRES-tTA)), a Flag-Pparg transcript and a wildtype transcript are detected by Northem blot analysis of white adipose tissue from heterozygotes. The fusion transcript of AF1-IRES-tTA is also detected in brown adipose tissue. Expression of tTA is detected in adipose tissue by Western blot analysis. No Flag-PPARG1 protein was detected in adipose tissue. Weak expression of tTA and the Flag-Pparg transcript is observed in placenta and liver. Endogenous PPARG2 protein is reduced in adipose tissues of heterozygotes. Heterozygotes exhibit "buffalo humps" (swollen interscapular fat pads swollen by hypertrophy and unilocular lipid deposition in mutant brown adipocytes), absence of subcutaneous adipocytes, reduced gonadal white adipose tissue, irregularly residual adipocyte shape and size, and fibrotic white adipose tissue stroma with leukocytic infiltration of the adipose tissue. Although, mutant mice have hyperinsulinemia, pancreatic islet hyperplasia, severe glucose intolerance, and hepatomegaly, they do not develop steatosis or type II diabetes. Prepubertal male heterozygotes exhibit hyperglycemia which normalizes with age. Treatment with doxycycline prevents this phenotype when administered starting at midgestation. A 6 week doxycycline treatment administered to pubertal heterozygotes reverses most of the phenotype, except the reduction in white adipose tissue. Mice that are homozygous for the targeted mutation are not viable. This mutant mouse strain may be useful in studies of lipodystrophy.

Development
The Ldi cassette, containing IRES sequence, tTA (tetracycline regulated transactivator), PGK-neo, polyA, and a flag-tagged Pparg (peroxisome proliferator activated receptor gamma) cDNA sequence, was used to replace exon 2. The construct was electroporated into 129S4/SvJae derived J1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. The resulting chimeric animals were crossed to 129S1/SvImJ mice. The Donating Investigator maintained the strain as a heterozygote because of the homozygous lethal phenotype.

Related Strains

Strains carrying other alleles of Pparg

004584	B6.129-Ppargtm2Rev/J
006142	B6.129S4-Ppargtm1Rev/J
008227	B6.129S4-Ppargtm3Yba/J

View Strains carrying other alleles of Pparg     (3 strains)

Additional Web Information

Tet Expression Systems

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

	Lipodystrophy, Congenital Generalized, Type 2; CGL2 - Models with phenotypic similarity to human disease where etiologies involve orthologs.1
	Lipodystrophy, Familial Partial, Type 3; FPLD3 - Models with phenotypic similarity to human disease where etiologies involve orthologs.1

1 Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Pparg^tm2Yba/Pparg⁺

        involves: 129S1/SvImJ * C57BL/6

• reproductive system phenotype
• reduced fertility (MGI Ref ID J:125992)
  • mice exhibit poor fecundity after introgression onto a C57BL/6 background
• adipose tissue phenotype
• *normal* adipose tissue phenotype (MGI Ref ID J:125992)
  • despite the development of dyslipidemia and severe insulin resistance, mice do not develop steatosis or type 2 diabetes
• abnormal brown adipose tissue morphology (MGI Ref ID J:125992)
  • mice exhibit hypertrophy and unilocular lipid deposition in mutant brown adipocytes
  • however, defects can be prevented by midgestational administration of doxycycline and reverted by a 6 week treatment with doxycycline
• abnormal gonadal fat pad morphology (MGI Ref ID J:125992)
  • gonadal fat pads are severely reduced compared to in wild-type mice
  • however, defects can be prevented by midgestational administration of doxycycline and reverted by a 6 week treatment with doxycycline
• abnormal interscapular fat pad morphology (MGI Ref ID J:125992)
  • mice exhibit 'buffalo humps' comprised of swollen interscapular fat pads due to hypertrophy and unilocular lipid deposition in mutant brown adipocytes
  • however, defects can be prevented by midgestational administration of doxycycline and reverted by a 6 week treatment with doxycycline
• abnormal white adipose tissue morphology (MGI Ref ID J:125992)
  • fibrotic white adipose tissue stroma is filled with fragmented lipid droplets and leukocytes
  • remaining adipocytes have irregular shapes and range in size from overtly hypertrophic to minuscule cells
  • however, defects were prevented by midgestational administration of doxycycline but adipocyte size does not revert following treatment with doxycycline
• decreased white adipose tissue amount (MGI Ref ID J:125992)
  • mice lack subcutaneous adipocytes
• adipocyte hypertrophy (MGI Ref ID J:125992)
  • mice exhibit hypertrophy in mutant brown adipocytes
  • however, defects can be prevented by midgestational administration of doxycycline and reverted by a 6 week treatment with doxycycline
• homeostasis/metabolism phenotype
• *normal* homeostasis/metabolism phenotype (MGI Ref ID J:125992)
  • despite the development of dyslipidemia and severe insulin resistance, mice do not develop steatosis or type 2 diabetes
• hyperglycemia (MGI Ref ID J:125992)
  • hyperglycemia develops prepuberty then normalizes latter in life with only sporadic and transient hyperglycemia
  • however, treatment with doxycycline reverses metabolic anomalies
• impaired glucose tolerance (MGI Ref ID J:125992)
  • mice exhibit severe glucose intolerance
  • however, treatment with doxycycline reverses metabolic anomalies
• increased circulating cholesterol level (MGI Ref ID J:125992)
  • mice exhibit an increase in serum cholesterol with early onset
  • however, treatment with doxycycline reverses metabolic anomalies
• increased circulating free fatty acid level (MGI Ref ID J:125992)
  • mice exhibit an increase in serum free fatty acids with early onset
  • however, treatment with doxycycline reverses metabolic anomalies
• increased circulating insulin level (MGI Ref ID J:125992)
  • mice exhibit an increase in serum insulin
  • however, treatment with doxycycline reverses metabolic anomalies
• increased circulating triglyceride level (MGI Ref ID J:125992)
  • mice exhibit an increase in serum triglycerides with early onset
  • however, treatment with doxycycline reverses metabolic anomalies
• insulin resistance (MGI Ref ID J:125992)
• endocrine/exocrine gland phenotype
• abnormal pancreas morphology (MGI Ref ID J:125992)
  • mice as old as 12 to 18 months exhibit hyperplastic with intact and insulin-laden pancreatic islets with hyperinsulinemia and normoglycemia
• islet cell hyperplasia (MGI Ref ID J:125992)
  • mice exhibit pancreas islet cell hyperplasia
  • however, treatment with doxycycline reverses metabolic anomalies
• liver/biliary system phenotype
• abnormal hepatocyte morphology (MGI Ref ID J:125992)
  • mice exhibit hepatocyte hypertrophy and vacuolization
• enlarged liver (MGI Ref ID J:125992)
  • liver size is increased by 60% to 150% and is accompanied by hepatocyte hypertrophy and vacuolization
  • however, lipid droplet accumulation is not observed
• digestive/alimentary phenotype
• abnormal pancreas morphology (MGI Ref ID J:125992)
  • mice as old as 12 to 18 months exhibit hyperplastic with intact and insulin-laden pancreatic islets with hyperinsulinemia and normoglycemia
• islet cell hyperplasia (MGI Ref ID J:125992)
  • mice exhibit pancreas islet cell hyperplasia
  • however, treatment with doxycycline reverses metabolic anomalies

View Research Applications

Research Applications

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

Developmental Biology Research
Embryonic Lethality (Homozygous)

Metabolism Research
Lipid Metabolism

Research Tools
Metabolism Research
Tet Expression Systems (tTA/rtTA Expressing Strains)
Tet Expression Systems (tTA/rtTA Responsive Strains)

Genes & Alleles

Gene & Allele Information

Allele Symbol		Ppargtm2Yba
Allele Name		targeted insertion 2, Yaacob Barak
Allele Type		Targeted (knock-in)
Common Name(s)		Ppargldi;
Mutation Made By		Yaacov Barak,   The Jackson Laboratory
Strain of Origin		129S4/SvJae
ES Cell Line Name		J1
ES Cell Line Strain		129S4/SvJae
Gene Symbol and Name		Pparg, peroxisome proliferator activated receptor gamma
Chromosome		6
Gene Common Name(s)		NR1C3; PPAR-gamma; PPARG1; PPARG2; PPARgamma; PPARgamma2; Ppar-gamma2;
Molecular Note		Exon 2 was replaced with an Idi cassette that contains an IRES-tTA, neo, poly-adenylation signal, TetO and flag-tagged cDNA. While expression is modest in adipose tissue, it is poor in the liver and placenta. [MGI Ref ID J:125992]

Genotyping

Genotyping Information

This strain will not have a genotyping protocol or one is not currently available.

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Kim S; Huang LW; Snow KJ; Ablamunits V; Hasham MG; Young TH; Paulk AC; Richardson JE; Affourtit JP; Shalom-Barak T; Bult CJ; Barak Y. 2007. A mouse model of conditional lipodystrophy. Proc Natl Acad Sci U S A 104(42):16627-32. [PubMed: 17921248]  [MGI Ref ID J:125992]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice can be bred as heterozygotes. Homozygotes are not viable. The Donating Investigator maintained the strain by crossing heterozygous males, between 3 and 5 months of age, to wildtype 129S1/SvImJ females. This strain has a problematic fecundity with only about half of the heterozygous male animals between 3 and 5 months of age reproducing.

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

 

This strain is currently Under Development for Distribution Colony.
To register your interest in this strain go to the Strain Interest Form.

Estimated Available for Sale Date:

Please note: Estimated available for sale 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 sale 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/interest registered.

View All Strains Under Development and On Hold

Supply Details

Standard Supply	Under Development for Distribution Colony
Supply Notes	This strain is included in the Induced Mutant Resource Colony collection.

General Terms and Conditions

See Terms of Use

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.

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Terms of Use

Terms of Use

General Terms and Conditions

Use of the Tet-System may require a license, see Licenses for Strains Using TET-System Technology.

Contact information

General inquiries

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phone:	207-288-6470
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