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 Chemically Induced Mutation; Congenic; Mutant Strain; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Species laboratory mouse Generation N8pN1 Generation Definitions   Donating Investigator John Schimenti,   Cornell University

Description
Mice homozygous for this ENU-induced F345I hypomorphic allele (Chaos3) are viable, fertile, and overtly indistinguishable from normal littermates. Homozygous, but not heterozygous, mice have slightly reduced wildtype protein levels in mouse embryonic fibroblasts (MEFs). Whereas Chaos3 heterozygotes show mildly elevated (2- to 5-fold) micronucleus frequencies compared with wildtype, homozygotes have an approximate 20-fold increase with over 7% of erythrocytes containing micronuclei. MEFs from homozygous mice exhibit mild defects (cell proliferation, S phase and G2/M populations), and are highly susceptible to chromosome breakage following treatment with the DNA replication inhibitor aphidicolin. On a congenic C3HeB/FeJ background, greater than 80% of homozygous females exhibit mammary adenocarcinomas with a mean latency of 12 months, while males have no tumor incidence. These Chaos3 mice provide a novel, non-transgenic model of breast cancer, and may be useful for studying of diagnostic pre-cancer cell markers, chromosomal instability and cell cycle checkpoint responses.

Development
Male C57BL/6J mice (Stock No. 000664) were treated with multidose N-ethyl-N-nitrosourea (ENU) and then bred to C3HeB/FeJ (Stock No. 000658). The resulting male pups were then bred to C3HeB/FeJ females to obtain second generation mice, which were subsequently intercrossed to obtain third generation mice. A mutagenesis screen was then performed to select mice for chromosome instability (as assessed by micronucleus levels in erythrocytes). One of these mutants in which the tendency to form micronuclei segregated in a monogenic, autosomal recessive manner was termed Chaos3 (or chromosome aberrations occurring spontaneously 3). Further studies revealed that Chaos3 is a hypomorphic allele of Mcm4, containing a T to A transversion at nucleotide 1033 of the coding region that defines an amino acid change from phenylalanine to isoleucine at residue 345 (F345I). These mice have been backcrossed to C3HeB/FeJ for at least 8 generations prior to arrival at The Jackson Laboratory.

Control Information

	Control
	Wild-type from the colony
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. Natural Killer Cell and Glucocorticoid Deficiency with DNA Repair Defect; NKGCD   (MCM4)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Mcm4^chaos3/Mcm4^chaos3

        C3.B6-Mcm4^chaos3

• tumorigenesis
• hepatocellular carcinoma
  • 1 female developed a hepatocellular carcinoma   (MGI Ref ID J:117494)
• increased mammary gland tumor incidence
  • females (majority are virgin) show a high susceptibility to development of mammary tumors   (MGI Ref ID J:117494)
• • mammary adenocarcinoma
    • 13/16 females develop mammary tumors with a latency of 12 months; five animals had more than one tumor   (MGI Ref ID J:117494)
    • 9/18 tumors were in thoracic mammary gland and 7/18 were in cervical mammary gland   (MGI Ref ID J:117494)
• lung adenocarcinoma
  • 2 mammary tumors metastasized to lung   (MGI Ref ID J:117494)

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

Mcm4^chaos3/Mcm4⁺

        involves: C57BL/6J

• cellular phenotype
• abnormal cell nucleus morphology
  • show 2- to 5-fold elevated micronucleus frequencies compared to wild-type   (MGI Ref ID J:117494)

Mcm4^chaos3/Mcm4^chaos3

        involves: C57BL/6J

• mortality/aging
• premature death
  • mice die sooner than Mcm3^{Gt(RRR002)Byg}/Mcm3⁺ Mcm4^chaos3/Mcm4^chaos3 mice   (MGI Ref ID J:165667)
• tumorigenesis
• increased lymphoma incidence
  • unlike Mcm3^{Gt(RRR002)Byg}/Mcm3⁺ Mcm4^chaos3/Mcm4^chaos3 mice   (MGI Ref ID J:165667)
• • T cell derived lymphoma
    • unlike Mcm3^{Gt(RRR002)Byg}/Mcm3⁺ Mcm4^chaos3/Mcm4^chaos3 mice   (MGI Ref ID J:165667)
• increased mammary gland tumor incidence
  • after 12 months of age compared with Mcm3^{Gt(RRR002)Byg}/ Mcm3⁺ Mcm4^chaos3/Mcm4^chaos3 mice   (MGI Ref ID J:165667)
• hematopoietic system phenotype
• abnormal erythrocyte morphology
  • >7% of erythrocytes contain micronuclei   (MGI Ref ID J:117494)
  • mice exhibit an increase in micronuclei containing red blood cells indicating increased genome instability compared with wild-type mice   (MGI Ref ID J:165667)
• cellular phenotype
• abnormal cell nucleus morphology
  • show 20-fold elevated micronucleus frequencies compared to wild-type   (MGI Ref ID J:117494)
• chromosomal instability
  • mice exhibit an increase in micronuclei containing red blood cells indicating increased genome instability compared with wild-type mice   (MGI Ref ID J:165667)

Mcm4^chaos3/Mcm4^chaos3

        involves: C3HeB/FeJ * C57BL/6J

• cellular phenotype
• abnormal cell cycle
  • there are a lower number of cells in S phase and slightly increased G2/M populations compared to controls   (MGI Ref ID J:117494)
• decreased cell proliferation
  • mouse embryonic fibroblasts (MEFs) show a mild defect in proliferation   (MGI Ref ID J:117494)

View Research Applications

Research Applications

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

Cancer Research
Increased Tumor Incidence
      Adenomas
      Mammary Gland Tumors
      Mammary Gland Tumors: females only
Other
      DNA Repair
      tumor metastasis
Tumor Suppressor Genes

Cell Biology Research
Cell Cycle Regulation
DNA Damage Response
Transcriptional Regulation

Hematological Research
Hematopoietic Defects

Research Tools
Cancer Research
Cell Biology Research
Hematological Research

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Mcm4chaos3
Allele Name		chromosomal aberration occurring spontaneously 3
Allele Type		Chemically induced (ENU)
Common Name(s)		Chaos3; Mcm4F345I;
Mutation Made By		John Schimenti,   Cornell University
Strain of Origin		C57BL/6J
Gene Symbol and Name		Mcm4, minichromosome maintenance deficient 4 homolog (S. cerevisiae)
Chromosome		16
Gene Common Name(s)		19G; AI325074; AU045576; CDC21; CDC54; Cdc21; Mcmd4; NKCD; NKGCD; P1-CDC21; cell division cycle 21 (S.pombe); expressed sequence AI325074; expressed sequence AU045576; hCdc21; mCdc21; mini chromosome maintenance deficient 4 homolog (S. cerevisiae);
Molecular Note		In an ENU mutagenesis screen, a de novo T->A transversion at nucleotide 1033 of the coding region occurred, creating a phenylalanine to isoleucine change at residue 345. [MGI Ref ID J:117494]

Genotyping

Genotyping Information

Genotyping Protocols

Mcm4^chaos3, Pyrosequencing

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Shima N; Alcaraz A; Liachko I; Buske TR; Andrews CA; Munroe RJ; Hartford SA; Tye BK; Schimenti JC. 2007. A viable allele of Mcm4 causes chromosome instability and mammary adenocarcinomas in mice. Nat Genet 39(1):93-8. [PubMed: 17143284]  [MGI Ref ID J:117494]

Shima N; Hartford SA; Duffy T; Wilson LA; Schimenti KJ; Schimenti JC. 2003. Phenotype-based identification of mouse chromosome instability mutants. Genetics 163(3):1031-40. [PubMed: 12663541]  [MGI Ref ID J:82700]

Additional References

Mcm4^chaos3 related

Bagley BN; Keane TM; Maklakova VI; Marshall JG; Lester RA; Cancel MM; Paulsen AR; Bendzick LE; Been RA; Kogan SC; Cormier RT; Kendziorski C; Adams DJ; Collier LS. 2012. A dominantly acting murine allele of Mcm4 causes chromosomal abnormalities and promotes tumorigenesis. PLoS Genet 8(11):e1003034. [PubMed: 23133403]  [MGI Ref ID J:194117]

Chuang CH; Wallace MD; Abratte C; Southard T; Schimenti JC. 2010. Incremental genetic perturbations to MCM2-7 expression and subcellular distribution reveal exquisite sensitivity of mice to DNA replication stress. PLoS Genet 6(9):. [PubMed: 20838603]  [MGI Ref ID J:165667]

Gineau L; Cognet C; Kara N; Lach FP; Dunne J; Veturi U; Picard C; Trouillet C; Eidenschenk C; Aoufouchi S; Alcais A; Smith O; Geissmann F; Feighery C; Abel L; Smogorzewska A; Stillman B; Vivier E; Casanova JL; Jouanguy E. 2012. Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency. J Clin Invest 122(3):821-32. [PubMed: 22354167]  [MGI Ref ID J:184567]

Hartford SA; Luo Y; Southard TL; Min IM; Lis JT; Schimenti JC. 2011. Minichromosome maintenance helicase paralog MCM9 is dispensible for DNA replication but functions in germ-line stem cells and tumor suppression. Proc Natl Acad Sci U S A 108(43):17702-7. [PubMed: 21987787]  [MGI Ref ID J:177420]

Hughes CR; Guasti L; Meimaridou E; Chuang CH; Schimenti JC; King PJ; Costigan C; Clark AJ; Metherell LA. 2012. MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans. J Clin Invest 122(3):814-20. [PubMed: 22354170]  [MGI Ref ID J:184565]

Kawabata T; Yamaguchi S; Buske T; Luebben SW; Wallace M; Matise I; Schimenti JC; Shima N. 2011. A reduction of licensed origins reveals strain-specific replication dynamics in mice. Mamm Genome 22(9-10):506-17. [PubMed: 21611832]  [MGI Ref ID J:177547]

Wallace MD; Pfefferle AD; Shen L; McNairn AJ; Cerami EG; Fallon BL; Rinaldi VD; Southard TL; Perou CM; Schimenti JC. 2012. Comparative oncogenomics implicates the neurofibromin 1 gene (NF1) as a breast cancer driver. Genetics 192(2):385-96. [PubMed: 22851646]  [MGI Ref ID J:193516]

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	When maintaining a live colony, heterozygous mice are bred to C3HeB/FeJ (Stock No. 000658) inbred mice or wildtype siblings. Homozygous mutant females develop mammary turmors with a high incidence by approximately one year of age. Breeding productivity in heterozygous female may decline with age.

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
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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