Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Mating System Homozygote x Homozygote         (Female x Male)   01-MAR-06 Species laboratory mouse Generation N5+N2F2 (10-JAN-11) Generation Definitions   Donating Investigator David Ron,   NYU School of Medicine

Description
Mice that are homozygous for the targeted mutation are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. No gene product (MRNA or protein) is detected by Northern or Western blot analysis of toxin challenged mouse embryonic fibroblasts (MEFs). MEFs and renal proximal tubular epithelial cells have decreased apoptosis in response to endoplasmic reticulum stress induced by the toxin, tunicamycin. Pancreatic islets cells are more resistant to nitric oxide induced apoptosis. MEFs exhibit a delayed onset of unfolded protein response (UPR) target gene expression when treated with tunicamycin. This mutant mouse strain may be useful in studies of apoptosis and pathogenesis due to endoplasmic reticulum stress. The Donating Investigator reports that lacZ activity is not detected.

Development
A targeting construct containing a NLS-lacZ cassette and a floxed PGK-Neo cassette was used to disrupt almost all the coding region in exons 3 and 4. The construct was electroporated into 129S6/SvEvTac derived W4 embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts. The floxed selection cassette was later removed by Cre recombinase excision by crossing the mice to a Cre deleter strain. The donating investigator stated that the resulting mice were then crossed to C57BL/6 mice (see SNP note below) for 5 generations.

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 the 26 of 27 markers throughout the genome suggested a C57BL/6 genetic background (1 segregating for 129 on Chromosome 1), at least 3 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 Information

	Control
	See control note:	C57BL/6J mice (Stock No. 000664) may be used as controls.
	000664 C57BL/6J
Considerations for Choosing Controls

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. Myxoid Liposarcoma   (DDIT3)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Ddit3^tm1Dron/Ddit3^tm1Dron

        B6.129-Ddit3^tm1Dron

• immune system phenotype
• abnormal macrophage activation involved in immune response
  • macrophages treated with excess lipoprotein-cholesterol or tunicamycin fail to exhibit an increase in IP3-induced calcium release unlike similarly wild-type   (MGI Ref ID J:153833)
• decreased macrophage apoptosis
  • under cholesterol loading conditions, macrophages treated exhibit less apoptosis compared with similarly treated wild-type macrophages   (MGI Ref ID J:153833)
• cellular phenotype
• decreased macrophage apoptosis
  • under cholesterol loading conditions, macrophages treated exhibit less apoptosis compared with similarly treated wild-type macrophages   (MGI Ref ID J:153833)

The following phenotype relates to a compound genotype created using this strain.
Contact JAX^® Services jaxservices@jax.org for customized breeding options.

Ddit3^tm1Dron/Ddit3^tm1Dron

        either: (involves: 129S/SvEv * 129S1/Sv * 129X1/SvJ) or (involves: 129S1/Sv * 129X1/SvJ * CD-1)

• cellular phenotype
• decreased apoptosis
  • MEFs prepared from E13.5 embryos exhibit less programmed cell death when challenged with agents that perturb ER function   (MGI Ref ID J:52729)
  • homozygotes treated with tunicamycin to induce ER stress and renal insufficiency exhibit decreased programmed cell death in the renal proximal tubular epithelium   (MGI Ref ID J:52729)
• homeostasis/metabolism phenotype
• abnormal response to injury
  • homozygotes treated with tunicamycin to induce ER stress and renal insufficiency exhibit decreased programmed cell death in the renal proximal tubular epithelium compared to controls despite impaired renal function   (MGI Ref ID J:52729)

Ddit3^tm1Dron/Ddit3^tm1Dron

        involves: 129S1/Sv * 129X1/SvJ * FVB/N

• immune system phenotype
• decreased susceptibility to viral infection
  • homozygotes infected with a neurovirulent virus, Moloney MLV-ts1, exhibit a small, but significant, delay of about 4.5 days in the incubation period of the disease that correlates with a decrease in early virus replication   (MGI Ref ID J:112354)

Ddit3^tm1Dron/Ddit3^tm1Dron

        involves: 129S1/Sv * 129X1/SvJ

• endocrine/exocrine gland phenotype
• *normal* endocrine/exocrine gland phenotype
  • homozygotes have a normal pancreas   (MGI Ref ID J:129974)

View Research Applications

Research Applications

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

Apoptosis Research
Endogenous Regulators
Extracellular Modulators

Cell Biology Research
DNA Damage Response

Research Tools
Apoptosis Research
Toxicology Research
      free radical research

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Ddit3tm2.1Dron
Allele Name		targeted mutation 2.1, David Ron
Allele Type		Targeted (Reporter)
Common Name(s)		CHOP::LacZ;
Strain of Origin		129S6/SvEvTac
Gene Symbol and Name		Ddit3, DNA-damage inducible transcript 3
Chromosome		10
Gene Common Name(s)		C/EBP homoologous protein 10; CEBPZ; CHOP; CHOP-10; CHOP10; GADD153;
Molecular Note		A NLS-lacZ cassette and a floxed PGK-Neo cassette replaced the coding region in parts of exons 3 and 4. Cre-emdiated recombination removed the neo cassette. [MGI Ref ID J:137887]

Genotyping

Genotyping Information

Genotyping Protocols

Ddit3^tm1Dron, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Genetic Resource Sciences at The Jackson Laboratory. 2008. Expression/Specificity patterns of Cre transgenes MGI Direct Data Submission :.  [MGI Ref ID J:137887]

Additional References

Ddit3^tm2.1Dron related

Chen CM; Wu CT; Chiang CK; Liao BW; Liu SH. 2012. C/EBP homologous protein (CHOP) deficiency aggravates hippocampal cell apoptosis and impairs memory performance. PLoS One 7(7):e40801. [PubMed: 22815824]  [MGI Ref ID J:189613]

Deslauriers AM; Afkhami-Goli A; Paul AM; Bhat RK; Acharjee S; Ellestad KK; Noorbakhsh F; Michalak M; Power C. 2011. Neuroinflammation and endoplasmic reticulum stress are coregulated by crocin to prevent demyelination and neurodegeneration. J Immunol 187(9):4788-99. [PubMed: 21964030]  [MGI Ref ID J:179506]

Lozon TI; Eastman AJ; Matute-Bello G; Chen P; Hallstrand TS; Altemeier WA. 2011. PKR-dependent CHOP induction limits hyperoxia-induced lung injury. Am J Physiol Lung Cell Mol Physiol 300(3):L422-9. [PubMed: 21186267]  [MGI Ref ID J:171168]

Moisoi N; Klupsch K; Fedele V; East P; Sharma S; Renton A; Plun-Favreau H; Edwards RE; Teismann P; Esposti MD; Morrison AD; Wood NW; Downward J; Martins LM. 2009. Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response. Cell Death Differ 16(3):449-64. [PubMed: 19023330]  [MGI Ref ID J:158086]

Murakami T; Ockinger J; Yu J; Byles V; McColl A; Hofer AM; Horng T. 2012. Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc Natl Acad Sci U S A 109(28):11282-7. [PubMed: 22733741]  [MGI Ref ID J:186406]

Pfaffenbach KT; Gentile CL; Nivala AM; Wang D; Wei Y; Pagliassotti MJ. 2010. Linking endoplasmic reticulum stress to cell death in hepatocytes: roles of C/EBP homologous protein and chemical chaperones in palmitate-mediated cell death. Am J Physiol Endocrinol Metab 298(5):E1027-35. [PubMed: 20159858]  [MGI Ref ID J:162886]

Posey KL; Coustry F; Veerisetty AC; Liu P; Alcorn JL; Hecht JT. 2012. Chop (Ddit3) Is Essential for D469del-COMP Retention and Cell Death in Chondrocytes in an Inducible Transgenic Mouse Model of Pseudoachondroplasia. Am J Pathol 180(2):727-37. [PubMed: 22154935]  [MGI Ref ID J:180513]

Wu J; Ruas JL; Estall JL; Rasbach KA; Choi JH; Ye L; Bostrom P; Tyra HM; Crawford RW; Campbell KP; Rutkowski DT; Kaufman RJ; Spiegelman BM. 2011. The unfolded protein response mediates adaptation to exercise in skeletal muscle through a PGC-1alpha/ATF6alpha complex. Cell Metab 13(2):160-9. [PubMed: 21284983]  [MGI Ref ID J:169564]

Zhang Y; Larade K; Jiang ZG; Ito S; Wang W; Zhu H; Bunn HF. 2010. The flavoheme reductase Ncb5or protects cells against endoplasmic reticulum stress-induced lipotoxicity. J Lipid Res 51(1):53-62. [PubMed: 19609006]  [MGI Ref ID J:157053]

Zhao L; Rosales C; Seburn K; Ron D; Ackerman SL. 2010. Alteration of the unfolded protein response modifies neurodegeneration in a mouse model of Marinesco-Sjogren syndrome. Hum Mol Genet 19(1):25-35. [PubMed: 19801575]  [MGI Ref ID J:154993]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX12

Colony Maintenance

Mating System	Homozygote x Homozygote         (Female x Male)   01-MAR-06
Diet Information	LabDiet® 5K52/5K67

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

General Supply Notes

• Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	See control note:	C57BL/6J mice (Stock No. 000664) may be used as controls.
	000664 C57BL/6J
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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