Description

Strain Information

Type Congenic; 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)   22-FEB-10 Species laboratory mouse Generation N11+F6 (05-JUL-11) Generation Definitions   Donating Investigator Junying Yuan,   Harvard Medical School

Description
Mice homozygous for this caspase-2 targeted mutation are viable and fertile. As the mutation deletes the QACRG active site and the caspase-2_S sequence of the endogenous enzyme, this deletion was shown to inactivate both the long and short form of caspase-2. As such, homozygous mice exhibit defects in regulation of apoptosis; including an enlarged oocyte reserve attributed to a germ cell-intrinsic death defect during prenatal ovarian development (resistance to oocyte cell death following complete cytokine starvation or exposure to an anticancer drug), as well as accelerated motor neuron cell death and defective B lymphoblast apoptosis. In addition, caspase-2-deficient mice exhibit characteristics of premature aging (including shortened maximum lifespan, impaired hair growth, increased bone loss, reduced body fat content, and higher hepatic levels of oxidized proteins). As caspase-2 acts as an upstream regulator of cell death in many cell types, caspase-2-deficient mice may be useful in studying negative and positive regulation of apoptosis, as well as oxidatively damaged cell clearance and aging.

Development
A targeting vector was designed to replace a 1.65 kb genomic fragment (including the exon that encodes the active site pentapeptide QACRG and part of the next exon that encodes the caspase-2_S sequence) of the endogenous gene with a PGKneo cassette. The construct was electroporated into 129S4/SvJae-derived J1 embryonic stem (ES) cells. The donating investigator reports that correctly targeted ES cells were injected into blastocysts and the resulting chimeric males were bred to C57BL/6J females. The donating investigator reported that mice harboring this caspase-2 mutation were backcrossed to C57BL/6J inbred mice for 7-10 generations (see SNP note below) prior to arrival at The Jackson Laboratory. Upon arrival, mice were bred with C57BL/6J inbred mice for at least one generation to establish the colony.

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. 2 of the 27 markers on Chromosomes 6 and 7 were segregating, while 1 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
	000664 C57BL/6J
Considerations for Choosing Controls

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

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

Casp2^tm1Yuan/Casp2^tm1Yuan

        involves: 129S4/SvJae * C57BL/6J * DBA/2

• cellular phenotype
• abnormal apoptosis
  • reduction in apoptosis of female germ cells and oocytes exhibit almost complete resistance to apoptosis induced by the chemotherapeutic drug doxorubicin   (MGI Ref ID J:47601)
  • programmed cell death of facial motor neurons is accelerated during development   (MGI Ref ID J:47601)
  • B lymphoblasts are more resistant to apoptosis induced by granzyme B and perforin than wild-type cells   (MGI Ref ID J:47601)
  • slight increase in apoptosis of sympathetic neurons from the superior cervical ganglia following deprivation of nerve growth factor   (MGI Ref ID J:47601)
• • abnormal B cell apoptosis
    • B lymphoblasts are more resistant to apoptosis induced by granzyme B and perforin than wild-type cells   (MGI Ref ID J:47601)
  • abnormal neuron apoptosis
    • programmed cell death of facial motor neurons is accelerated during development   (MGI Ref ID J:47601)
    • slight increase in apoptosis of sympathetic neurons from the superior cervical ganglia following deprivation of nerve growth factor   (MGI Ref ID J:47601)
• reproductive system phenotype
• abnormal female germ cell morphology
  • increase in numbers of germ cells in the ovaries due to reduced apoptosis   (MGI Ref ID J:47601)
• • abnormal oocyte morphology
    • increase in the number of oocytes due to reduced apoptosis in the female germline   (MGI Ref ID J:47601)
    • oocytes exhibit almost complete resistance to apoptosis induced by the chemotherapeutic drug doxorubicin   (MGI Ref ID J:47601)
• abnormal primordial ovarian follicle morphology
  • increase in the number of primordial follicles in the postnatal ovary   (MGI Ref ID J:47601)
• nervous system phenotype
• abnormal facial motor nucleus morphology
  • number of motor neurons in the facial nuclei of late embryonic and newborn mutants is only 73% of that in wild-type, however, normal numbers are seen at E16.5 and at P7-P9, suggesting that programmed cell death of facial motor neurons is accelerated during development but eventually similar numbers of neurons die   (MGI Ref ID J:47601)
• abnormal neuron apoptosis
  • programmed cell death of facial motor neurons is accelerated during development   (MGI Ref ID J:47601)
  • slight increase in apoptosis of sympathetic neurons from the superior cervical ganglia following deprivation of nerve growth factor   (MGI Ref ID J:47601)
• abnormal sympathetic neuron morphology
  • slight increase in apoptosis of sympathetic neurons from the superior cervical ganglia following deprivation of nerve growth factor   (MGI Ref ID J:47601)
• endocrine/exocrine gland phenotype
• abnormal primordial ovarian follicle morphology
  • increase in the number of primordial follicles in the postnatal ovary   (MGI Ref ID J:47601)
• immune system phenotype
• abnormal B cell apoptosis
  • B lymphoblasts are more resistant to apoptosis induced by granzyme B and perforin than wild-type cells   (MGI Ref ID J:47601)

View Research Applications

Research Applications

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

Apoptosis Research
Endogenous Regulators
Extracellular Modulators

Cancer Research
Growth Factors/Receptors/Cytokines

Cell Biology Research
Post-translational Processing
Protein Processing
Signal Transduction

Developmental Biology Research
Internal/Organ Defects
      gonads

Immunology and Inflammation Research
Growth Factors/Receptors/Cytokines
Intracellular Signaling Molecules

Reproductive Biology Research
Developmental Defects Affecting Gonads

Research Tools
Apoptosis Research
Cell Biology Research
Reproductive Biology Research
      oocyte

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Casp2tm1Yuan
Allele Name		targeted mutation 1, Junying Yuan
Allele Type		Targeted (knock-out)
Mutation Made By		Junying Yuan,   Harvard Medical School
Strain of Origin		129S4/SvJae
ES Cell Line Name		J1
ES Cell Line Strain		129S4/SvJae
Gene Symbol and Name		Casp2, caspase 2
Chromosome		6
Gene Common Name(s)		CASP-2; Caspase-2; ICH1; Ich-1; NEDD-2; NEDD2; Nedd2; PPP1R57; neural precursor cell expressed, developmentally down-regulated gene 2;
Molecular Note		A neomycin selection cassette replaced a 1.65 kb genomic fragment containing sequences that encode part of the active site of the protein and other essential regions. RT-PCR analysis on spleen mRNA derived from homozygous mice demonstrated that no detectable transcript is expressed from this allele, and western blot analysis on lysates derived from various tissues of homozygous mice confirmed that no detectable protein was encoded. [MGI Ref ID J:47601]

Genotyping

Genotyping Information

Genotyping Protocols

Casp2^tm1Yaun MCA, Melt Curve Analysis
Casp2^tm1Yuan, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Bergeron L; Perez GI; Macdonald G; Shi L; Sun Y; Jurisicova A; Varmuza S; Latham KE; Flaws JA; Salter JC; Hara H; Moskowitz MA; Li E; Greenberg A; Tilly JL; Yuan J. 1998. Defects in regulation of apoptosis in caspase-2-deficient mice. Genes Dev 12(9):1304-14. [PubMed: 9573047]  [MGI Ref ID J:47601]

Morita Y; Maravei DV; Bergeron L; Wang S; Perez GI; Tsutsumi O; Taketani Y; Asano M; Horai R; Korsmeyer SJ; Iwakura Y; Yuan J; Tilly JL. 2001. Caspase-2 deficiency prevents programmed germ cell death resulting from cytokine insufficiency but not meiotic defects caused by loss of ataxia telangiectasia-mutated (Atm) gene function. Cell Death Differ 8(6):614-20. [PubMed: 11536012]  [MGI Ref ID J:115619]

Additional References

Casp2^tm1Yuan related

Berube C; Boucher LM; Ma W; Wakeham A; Salmena L; Hakem R; Yeh WC; Mak TW; Benchimol S. 2005. Apoptosis caused by p53-induced protein with death domain (PIDD) depends on the death adapter protein RAIDD. Proc Natl Acad Sci U S A 102(40):14314-20. [PubMed: 16183742]  [MGI Ref ID J:101402]

Tiwari M; Herman B; Morgan WW. 2011. A knockout of the caspase 2 gene produces increased resistance of the nigrostriatal dopaminergic pathway to MPTP-induced toxicity. Exp Neurol 229(2):421-8. [PubMed: 21419766]  [MGI Ref ID J:172690]

Tiwari M; Lopez-Cruzan M; Morgan WW; Herman B. 2011. Loss of caspase-2-dependent apoptosis induces autophagy after mitochondrial oxidative stress in primary cultures of young adult cortical neurons. J Biol Chem 286(10):8493-506. [PubMed: 21216964]  [MGI Ref ID J:170658]

Troy CM; Rabacchi SA; Hohl JB; Angelastro JM; Greene LA; Shelanski ML. 2001. Death in the balance: alternative participation of the caspase-2 and -9 pathways in neuronal death induced by nerve growth factor deprivation. J Neurosci 21(14):5007-16. [PubMed: 11438576]  [MGI Ref ID J:124514]

Tu S; McStay GP; Boucher LM; Mak T; Beere HM; Green DR. 2006. In situ trapping of activated initiator caspases reveals a role for caspase-2 in heat shock-induced apoptosis. Nat Cell Biol 8(1):72-7. [PubMed: 16362053]  [MGI Ref ID J:129408]

Zhang Y; Padalecki SS; Chaudhuri AR; De Waal E; Goins BA; Grubbs B; Ikeno Y; Richardson A; Mundy GR; Herman B. 2007. Caspase-2 deficiency enhances aging-related traits in mice. Mech Ageing Dev 128(2):213-21. [PubMed: 17188333]  [MGI Ref ID J:119928]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           MGL377

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, homozygous may may be bred.
Mating System	Homozygote x Homozygote         (Female x Male)   22-FEB-10
Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls

General Supply Notes

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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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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