Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

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. Species laboratory mouse Generation N11F1N1p (30-MAY-04) Generation Definitions   Donating Investigator Peter K. Sorger,   Massachusetts Institute of Technology

Description
Mice that are heterozygous for the Mad2l1^tm1Sorg targeted allele are viable, fertile, normal in size, and do not display any gross physical or behavioral abnormalities. Homozygous null mice are embryonic lethal; they fail to develop past embryonic days 6-7 due to catastrophic chromosome missegregation and apoptosis. Histological analysis of heterozygous mutant mice reveal increased germinal center formation in spleen and a higher incidence of lung carcinomas when compared to the wildtype. This mutant mouse strain represents a model that may be useful in studies of the role cell-division checkpoints in tumorogenesis.

Development
A targeting vector containing neomycin resistance gene driven by the mouse phosphoglycerate kinase promoter and herpes simplex virus thymidine kinase genes was used to disrupt all coding sequence of the targeted gene. The construct was electroporated into 129S2/SvPas derived D3 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts.

Control Information

	Control
	Wild-type from the colony
	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.

Mad2l1^tm1Sorg/Mad2l1⁺

        involves: 129S2/SvPas * C57BL/6

• tumorigenesis
• lung adenocarcinoma
  • at 18-19 months of age, heterozygotes show a high frequency of papillary lung adenocarcinomas relative to age-matched wild-type mice   (MGI Ref ID J:67456)
  • in contrast, the background rate of lymphomas detected in ageing heterozygotes remains unchanged relative to wild-type   (MGI Ref ID J:67456)
• cellular phenotype
• *normal* cellular phenotype
  • initial studies indicated that heterozygotes develop normally, with blastocysts exhibiting no evidence of a defective mitotic checkpoint as assayed by reactivity to phospho-histone 3 antibody; premature sister-chromatid separation was not examined in initial experiments   (MGI Ref ID J:62829)
• • chromosome breakage
    • MEFs from 4 out of 5 heterozygotes exhibit high frequencies of premature anaphase (sister-chromatid separation) relative to wild-type cultures   (MGI Ref ID J:67456)
    • all heterozygous MEF cultures display a significant increase in the number of aneuploid cells relative to wild-type cultures   (MGI Ref ID J:67456)
    • the % of aneuploid cells correlates with the severity of premature anaphase, suggesting a direct relationship between the severity of loss of checkpoint control and chromosome mis-segregation   (MGI Ref ID J:67456)
• hematopoietic system phenotype
• increased spleen germinal center number
  • heterozygotes are viable and largely normal but exhibit atypical (increased) germinal center formation in spleen relative to wild-type mice   (MGI Ref ID J:62829)
• immune system phenotype
• increased spleen germinal center number
  • heterozygotes are viable and largely normal but exhibit atypical (increased) germinal center formation in spleen relative to wild-type mice   (MGI Ref ID J:62829)

Mad2l1^tm1Sorg/Mad2l1⁺

        involves: 129S2/SvPas

• cellular phenotype
• abnormal cell physiology
  • 7.2% of MEFs are aneuploid for chromosome 2 compared to 1.4% of wild-type MEFs   (MGI Ref ID J:117337)
  • mutant MEFs injected into athymic nude mice produced tumors in 8/8 mice within 4 weeks compared to no tumors from wild-type MEFs; tumors are 40% smaller at 6 weeks compared to than produced by MEFs from Mad1/Mad2 mutants   (MGI Ref ID J:117337)
• abnormal chromosome number
  • chromosomal instability is much higher than in wild-type MEFs   (MGI Ref ID J:117337)
• • aneuploidy   (MGI Ref ID J:117337)
    • at 5 months of age 15% of splenocytes are aneuploid; however no early aging related phenotypes are seen in heterozygotes at 19 to 27 months of age and no increase in the number of senescent MEFs is seen compared to wild-type   (MGI Ref ID J:105717)
• tumorigenesis
• increased incidence of induced tumors
  • mutant MEFs induce tumors in 100% of athymic nude mice in 4 weeks   (MGI Ref ID J:117337)

Mad2l1^tm1Sorg/Mad2l1^tm1Sorg

        involves: 129S2/SvPas * C57BL/6

• mortality/aging
• complete embryonic lethality between implantation and somite formation
  • homozygous mutant embryos die in utero between E6.5 and E7.5   (MGI Ref ID J:62829)
• cellular phenotype
• abnormal inner cell mass apoptosis
  • in vitro, cell death is restricted to the rapidly dividing cells of the inner cell mass   (MGI Ref ID J:62829)
• abnormal inner cell mass proliferation
  • in vitro, the ICM of mutant embryos stops proliferating after E6.5 and virtually no mutant ICM cells persist to E8.5   (MGI Ref ID J:62829)
  • in contrast, the postmitotic and highly polyploid trophoblast giant cells continue to grow in size through E8.5   (MGI Ref ID J:62829)
• abnormal mitosis
  • strikingly, ~25% of mitotic cells contain one or more lagging chromosomes, suggesting that anaphase proceeds in the absence of complete chromosome-microtubule attachment   (MGI Ref ID J:62829)
  • in utero, E6.5-E7.5 mutant embryos show a significant reduction in the total number of mitotic cells   (MGI Ref ID J:62829)
• • abnormal mitotic spindle assembly checkpoint
    • at E5.5, mutant embryonic cells assemble normal spindles and undergo mitosis but are unable to arrest in response to drug-induced spindle disruption, indicating loss of a functional spindle assembly checkpoint   (MGI Ref ID J:62829)
    • absence of a functional spindle assembly checkpoint allows mutant cells to proceed even when unattached chromosomes are present, resulting in widespread chromosome missegregation   (MGI Ref ID J:62829)
• increased apoptosis
  • mutant embryos undergo programmed cell death after the initiation of gastrulation at E6.5-E7.5; at this stage, wild-type embryos contain only a few apoptotic cells near the embryo center   (MGI Ref ID J:62829)
• embryogenesis phenotype
• *normal* embryogenesis phenotype
  • homozygous mutant embryos appear normal both in utero and in culture until E5.5   (MGI Ref ID J:62829)
• • abnormal embryonic tissue morphology
    • mutant embryos appear grossly abnormal relative to wild-type embryos   (MGI Ref ID J:62829)
  • abnormal inner cell mass apoptosis
    • in vitro, cell death is restricted to the rapidly dividing cells of the inner cell mass   (MGI Ref ID J:62829)
  • abnormal inner cell mass proliferation
    • in vitro, the ICM of mutant embryos stops proliferating after E6.5 and virtually no mutant ICM cells persist to E8.5   (MGI Ref ID J:62829)
    • in contrast, the postmitotic and highly polyploid trophoblast giant cells continue to grow in size through E8.5   (MGI Ref ID J:62829)
  • decreased embryo size
    • mutant embryos are small relative to wild-type embryos   (MGI Ref ID J:62829)
• growth/size phenotype
• decreased embryo size
  • mutant embryos are small relative to wild-type embryos   (MGI Ref ID J:62829)

View Research Applications

Research Applications

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

Mad2l1^tm1Sorg related

Apoptosis Research
Endogenous Regulators

Cancer Research
Increased Tumor Incidence
      Other Tissues/Organs
      Other Tissues/Organs: lung

Cell Biology Research
Cell Cycle Regulation

Developmental Biology Research
Embryonic Lethality (Homozygous)

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Mad2l1tm1Sorg
Allele Name		targeted mutation 1, Peter K Sorger
Allele Type		Targeted (knock-out)
Common Name(s)		Mad2-;
Mutation Made By		Max Dobles,   Biogen Inc
Strain of Origin		129S2/SvPas
ES Cell Line Name		D3
ES Cell Line Strain		129S2/SvPas
Gene Symbol and Name		Mad2l1, MAD2 mitotic arrest deficient-like 1
Chromosome		6
Gene Common Name(s)		AA673185; HSMAD2; MAD2; expressed sequence AA673185;
Molecular Note		A PGK-neomycin resistance cassette replaced the entire coding region. [MGI Ref ID J:62829]

Genotyping

Genotyping Information

Genotyping Protocols

Mad2l1^tm1Sorg, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Dobles M; Liberal V; Scott ML; Benezra R; Sorger PK. 2000. Chromosome missegregation and apoptosis in mice lacking the mitotic checkpoint protein Mad2. Cell 101(6):635-45. [PubMed: 10892650]  [MGI Ref ID J:62829]

Additional References

Mad2l1^tm1Sorg related

Baker DJ; Jeganathan KB; Malureanu L; Perez-Terzic C; Terzic A; van Deursen JM. 2006. Early aging-associated phenotypes in Bub3/Rae1 haploinsufficient mice. J Cell Biol 172(4):529-40. [PubMed: 16476774]  [MGI Ref ID J:105717]

Burds AA; Lutum AS; Sorger PK. 2005. Generating chromosome instability through the simultaneous deletion of Mad2 and p53. Proc Natl Acad Sci U S A 102(32):11296-301. [PubMed: 16055552]  [MGI Ref ID J:100464]

Chi YH; Ward JM; Cheng LI; Yasunaga J; Jeang KT. 2009. Spindle assembly checkpoint and p53 deficiencies cooperate for tumorigenesis in mice. Int J Cancer 124(6):1483-9. [PubMed: 19065665]  [MGI Ref ID J:147512]

Foijer F; DiTommaso T; Donati G; Hautaviita K; Xie SZ; Heath E; Smyth I; Watt FM; Sorger PK; Bradley A. 2013. Spindle checkpoint deficiency is tolerated by murine epidermal cells but not hair follicle stem cells. Proc Natl Acad Sci U S A 110(8):2928-33. [PubMed: 23382243]  [MGI Ref ID J:194539]

Ito S; Mantel CR; Han MK; Basu S; Fukuda S; Cooper S; Broxmeyer HE. 2007. Mad2 is required for optimal hematopoiesis: Mad2 associates with c-Kit in MO7e cells. Blood 109(5):1923-30. [PubMed: 17038523]  [MGI Ref ID J:145365]

Iwanaga Y; Chi YH; Miyazato A; Sheleg S; Haller K; Peloponese JM Jr; Li Y; Ward JM; Benezra R; Jeang KT. 2007. Heterozygous deletion of mitotic arrest-deficient protein 1 (MAD1) increases the incidence of tumors in mice. Cancer Res 67(1):160-6. [PubMed: 17210695]  [MGI Ref ID J:117337]

Michel LS; Liberal V; Chatterjee A; Kirchwegger R; Pasche B; Gerald W; Dobles M; Sorger PK; Murty VV; Benezra R. 2001. MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells. Nature 409(6818):355-9. [PubMed: 11201745]  [MGI Ref ID J:67456]

Niault T; Hached K; Sotillo R; Sorger PK; Maro B; Benezra R; Wassmann K. 2007. Changing mad2 levels affects chromosome segregation and spindle assembly checkpoint control in female mouse meiosis I. PLoS ONE 2(11):e1165. [PubMed: 18043727]  [MGI Ref ID J:130342]

Rohrabaugh SL; Hangoc G; Kelley MR; Broxmeyer HE. 2011. Mad2 haploinsufficiency protects hematopoietic progenitor cells subjected to cell-cycle stress in vivo and to inhibition of redox function of Ape1/Ref-1 in vitro. Exp Hematol 39(4):415-23. [PubMed: 21216274]  [MGI Ref ID J:171833]

Zhang Y; Foreman O; Wigle DA; Kosari F; Vasmatzis G; Salisbury JL; van Deursen J; Galardy PJ. 2012. USP44 regulates centrosome positioning to prevent aneuploidy and suppress tumorigenesis. J Clin Invest 122(12):4362-74. [PubMed: 23187126]  [MGI Ref ID J:193965]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200.

Colony Maintenance

Breeding & Husbandry

The resulting chimeric animals were crossed to C57BL/6 mice, and then backcrossed to the same for 10 generations (3/02). This strain is maintained as a heterozygote. Homozygous mutant mice have an embryonic lethal phenotype, failing to develop past embryonic days 6-7. Donating Investigator reports reproductive performance of heterozygotes is normal and recommends breeding heterozygotes at approximately 2 months of age; continue to breed for at least 18 months.

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
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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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.

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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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