Description

Strain Information

Type Congenic; Mutant Strain; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Mating System Wild-type x Heterozygote         (Female x Male)   12-DEC-12 Mating System Heterozygote x Wild-type         (Female x Male)   12-DEC-12 Species laboratory mouse Generation +pN1+N1 (20-MAR-13) Generation Definitions   Donating Investigator Beth Levine,   University of Texas Southwestern Medical

Description
Monoallelic deletion of the autophagy related beclin 1 (Becn1) gene is associated with 40-75% of human breast, ovarian and prostate cancers. 30% of mice heterozygous for the Becn1 allele exhibit tumors by 13-18 months of age. Tumor types include: lung carcinomas, hepatocellular carcinomas and lymphomas. In addition, mice develop hepatitis B virus-induced neoplasia, increased cellular proliferation and reduced autophagy. Homozygous deletion of the targeted allele results in embryonic lethality. Of note, mice on a C57BL/6 background have a brown coat color which is believed to be a result of the effect of the Becn1 mutation on melanogenesis. These mice may be useful for studies involving autophagy and negative cell growth and tumor suppression.

Development
A targeting vector was designed to replace exons 1 and 2 with a neomycin resistance (neo) cassette. The construct was electroporated into 129X1/SvJ-derived embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts and the resulting chimeric mice were bred to C57BL/6. Offspring were backcrossed to C57BL/6 for 50 generations, however, mice retain a brown coat color, which is believed to be a result of the role of Becn1 in melanogenesis. Upon arrival, mice were bred to C57BL/6J inbred mice (Stock No. 000664) for at least one generation to establish the colony.

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.

Becn1^tm1Blev/Becn1⁺

        involves: 129X1/SvJ * C57BL/6J

• mortality/aging
• premature death
  • mutants show some tumor-associated mortality at 6 to 8 months of age   (MGI Ref ID J:86953)
• tumorigenesis
• increased tumor incidence
  • 15% of mutants at 13-18 months of age exhibit palpable tumors compared to 1% of wild-type mice   (MGI Ref ID J:86953)
• • increased lung adenoma incidence
    • mutants have an increased frequency of lung lesions in earlier stages of neoplasia, including hyperplastic alveolar epithelium resembling human atypical adenomatous hyperplasia and bronchioalveolar adenomas composed of monomorphous cells with minimal cytologic atypia   (MGI Ref ID J:86953)
  • increased lymphoma incidence
    • develop lymphomas that occur more frequently, at an earlier age, are more likely to present as palpable masses than in wild-type, including diffuse large-cell lymphoma, follicular lymphoma, immunoblastic variant of diffuse large-cell lymphoma, anaplastic plasmacytoma, and histiocytic sarcoma   (MGI Ref ID J:86953)
  • • follicular lymphoma   (MGI Ref ID J:86953)
    • increased histiocytic sarcoma incidence   (MGI Ref ID J:86953)
  • increased mammary gland tumor incidence
    • proliferative lesions (mammary intraepithelial neoplasia, adenomyoepithelioma, and acinar neoplasia) are present in mammary gland of 13 to 18 month old mutants   (MGI Ref ID J:86953)
  • increased plasmacytoma incidence
    • anaplastic plasmacytoma   (MGI Ref ID J:86953)
  • malignant tumors
    • mutants have a higher probability of having a malignancy (30%) than wild-type (14%); malignancies do not contain mutations in the wild-type Becn1 allele   (MGI Ref ID J:86953)
  • • hepatocellular carcinoma
      • well-differentiated hepatocellular carcinomas   (MGI Ref ID J:86953)
    • increased histiocytic sarcoma incidence   (MGI Ref ID J:86953)
    • lung carcinoma
      • greater number of and larger lung carcinomas than in wild-type mice   (MGI Ref ID J:86953)
    • • lung adenocarcinoma
        • lung cancers show features of well-differentiated human papillary adenocarcinomas   (MGI Ref ID J:86953)
• cellular phenotype
• abnormal autophagy
  • germinal center B lymphocytes have fewer autophagic vacuoles than wild-type lymphocytes 10 days after immunization with sheep red blood cells, indicating reduced autophagic activity   (MGI Ref ID J:86953)
• endocrine/exocrine gland phenotype
• abnormal mammary gland duct morphology
  • mammary ducts are frequently abnormal, with multiple layers of epithelial cells and intraluminal collections of epithelial cells   (MGI Ref ID J:86953)
  • hyperproliferation of mammary ductal epithelial cells in the terminal end buds   (MGI Ref ID J:86953)
  • mammary ducts show increase in DNA synthesis   (MGI Ref ID J:86953)
• hematopoietic system phenotype
• increased spleen germinal center number
  • mutants show an increase in the number of germinal centeres in the spleens following immunization with sheep red blood cells at 2 months of age   (MGI Ref ID J:86953)
• increased spleen germinal center size
  • mutants show an increase in the size of germinal centers in the spleens following immunization with sheep red blood cells at 2 months of age   (MGI Ref ID J:86953)
• immune system phenotype
• abnormal immune system morphology
  • increase in frequency of extranodal, splenic, and nodal lymphoproliferative disease   (MGI Ref ID J:86953)
• • increased spleen germinal center number
    • mutants show an increase in the number of germinal centeres in the spleens following immunization with sheep red blood cells at 2 months of age   (MGI Ref ID J:86953)
  • increased spleen germinal center size
    • mutants show an increase in the size of germinal centers in the spleens following immunization with sheep red blood cells at 2 months of age   (MGI Ref ID J:86953)
• integument phenotype
• abnormal mammary gland duct morphology
  • mammary ducts are frequently abnormal, with multiple layers of epithelial cells and intraluminal collections of epithelial cells   (MGI Ref ID J:86953)
  • hyperproliferation of mammary ductal epithelial cells in the terminal end buds   (MGI Ref ID J:86953)
  • mammary ducts show increase in DNA synthesis   (MGI Ref ID J:86953)

Becn1^tm1Blev/Becn1^tm1Blev

        involves: 129X1/SvJ * C57BL/6J

• mortality/aging
• complete prenatal lethality
  • embryonic lethality, time not specified   (MGI Ref ID J:86953)

Becn1^tm1Blev/Becn1^tm1Blev

        involves: 129X1/SvJ

• cardiovascular system phenotype
• decreased myocardial infarction size
  • following ischemia and reperfusion with SB216763 (a GSK3b inhibitor) and rapamycin treatment   (MGI Ref ID J:186597)
• increased myocardial infarction size
  • following 2 hours of ischemia without reperfusion   (MGI Ref ID J:186597)
  • not affected by treatment with SB216763 (a GSK3b inhibitor) and rapamycin   (MGI Ref ID J:186597)
• homeostasis/metabolism phenotype
• decreased myocardial infarction size
  • following ischemia and reperfusion with SB216763 (a GSK3b inhibitor) and rapamycin treatment   (MGI Ref ID J:186597)
• increased myocardial infarction size
  • following 2 hours of ischemia without reperfusion   (MGI Ref ID J:186597)
  • not affected by treatment with SB216763 (a GSK3b inhibitor) and rapamycin   (MGI Ref ID J:186597)

View Research Applications

Research Applications

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

Cancer Research
Increased Tumor Incidence
      Adenomas: lung
      Hepatomas: hepatacellular carcinoma
      Lymphomas

Developmental Biology Research
Embryonic Lethality (Homozygous)

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Becn1tm1Blev
Allele Name		targeted mutation 1, Beth Levine
Allele Type		Targeted (knock-out)
Common Name(s)		beclin 1-;
Mutation Made By		Beth Levine,   University of Texas Southwestern Medical
Strain of Origin		129X1/SvJ
Gene Symbol and Name		Becn1, beclin 1, autophagy related
Chromosome		11
Gene Common Name(s)		ATG6; MGC:6843; VPS30; beclin1;
Molecular Note		Exons 1 and 2 were replace with a neomycin selection cassette inserted by homologous recombination. [MGI Ref ID J:86953]

Genotyping

Genotyping Information

Genotyping Protocols

Becn1^tm1Blev,

Separated MCA

Becn1^tm1Blev, Separated PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Qu X; Yu J; Bhagat G; Furuya N; Hibshoosh H; Troxel A; Rosen J; Eskelinen EL; Mizushima N; Ohsumi Y; Cattoretti G; Levine B. 2003. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 112(12):1809-20. [PubMed: 14638851]  [MGI Ref ID J:86953]

Additional References

Becn1^tm1Blev related

Fujimoto K; Hanson PT; Tran H; Ford EL; Han Z; Johnson JD; Schmidt RE; Green KG; Wice BM; Polonsky KS. 2009. Autophagy regulates pancreatic beta cell death in response to Pdx1 deficiency and nutrient deprivation. J Biol Chem 284(40):27664-73. [PubMed: 19654319]  [MGI Ref ID J:155712]

Germain M; Nguyen AP; Le Grand JN; Arbour N; Vanderluit JL; Park DS; Opferman JT; Slack RS. 2011. MCL-1 is a stress sensor that regulates autophagy in a developmentally regulated manner. EMBO J 30(2):395-407. [PubMed: 21139567]  [MGI Ref ID J:168794]

Hariharan N; Ikeda Y; Hong C; Alcendor RR; Usui S; Gao S; Maejima Y; Sadoshima J. 2013. Autophagy plays an essential role in mediating regression of hypertrophy during unloading of the heart. PLoS One 8(1):e51632. [PubMed: 23308102]  [MGI Ref ID J:195814]

He C; Bassik MC; Moresi V; Sun K; Wei Y; Zou Z; An Z; Loh J; Fisher J; Sun Q; Korsmeyer S; Packer M; May HI; Hill JA; Virgin HW; Gilpin C; Xiao G; Bassel-Duby R; Scherer PE; Levine B. 2012. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481(7382):511-5. [PubMed: 22258505]  [MGI Ref ID J:181308]

Kim SI; Na HJ; Ding Y; Wang Z; Lee SJ; Choi ME. 2012. Autophagy promotes intracellular degradation of type I collagen induced by transforming growth factor (TGF)-beta1. J Biol Chem 287(15):11677-88. [PubMed: 22351764]  [MGI Ref ID J:184288]

Matsui Y; Takagi H; Qu X; Abdellatif M; Sakoda H; Asano T; Levine B; Sadoshima J. 2007. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res 100(6):914-22. [PubMed: 17332429]  [MGI Ref ID J:133796]

Nakahira K; Haspel JA; Rathinam VA; Lee SJ; Dolinay T; Lam HC; Englert JA; Rabinovitch M; Cernadas M; Kim HP; Fitzgerald KA; Ryter SW; Choi AM. 2011. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol 12(3):222-30. [PubMed: 21151103]  [MGI Ref ID J:169252]

Niu H; Xiong Q; Yamamoto A; Hayashi-Nishino M; Rikihisa Y. 2012. Autophagosomes induced by a bacterial Beclin 1 binding protein facilitate obligatory intracellular infection. Proc Natl Acad Sci U S A 109(51):20800-7. [PubMed: 23197835]  [MGI Ref ID J:193111]

Parkhitko A; Myachina F; Morrison TA; Hindi KM; Auricchio N; Karbowniczek M; Wu JJ; Finkel T; Kwiatkowski DJ; Yu JJ; Henske EP. 2011. Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent. Proc Natl Acad Sci U S A 108(30):12455-60. [PubMed: 21746920]  [MGI Ref ID J:174534]

Pickford F; Masliah E; Britschgi M; Lucin K; Narasimhan R; Jaeger PA; Small S; Spencer B; Rockenstein E; Levine B; Wyss-Coray T. 2008. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest 118(6):2190-9. [PubMed: 18497889]  [MGI Ref ID J:137727]

Portillo JA; Okenka G; Reed E; Subauste A; Van Grol J; Gentil K; Komatsu M; Tanaka K; Landreth G; Levine B; Subauste CS. 2010. The CD40-autophagy pathway is needed for host protection despite IFN-Gamma-dependent immunity and CD40 induces autophagy via control of P21 levels. PLoS One 5(12):e14472. [PubMed: 21217818]  [MGI Ref ID J:168250]

Tannous P; Zhu H; Johnstone JL; Shelton JM; Rajasekaran NS; Benjamin IJ; Nguyen L; Gerard RD; Levine B; Rothermel BA; Hill JA. 2008. Autophagy is an adaptive response in desmin-related cardiomyopathy. Proc Natl Acad Sci U S A 105(28):9745-50. [PubMed: 18621691]  [MGI Ref ID J:137839]

Zhai P; Sciarretta S; Galeotti J; Volpe M; Sadoshima J. 2011. Differential roles of GSK-3beta during myocardial ischemia and ischemia/reperfusion. Circ Res 109(5):502-11. [PubMed: 21737790]  [MGI Ref ID J:186597]

Zhu H; Tannous P; Johnstone JL; Kong Y; Shelton JM; Richardson JA; Le V; Levine B; Rothermel BA; Hill JA. 2007. Cardiac autophagy is a maladaptive response to hemodynamic stress. J Clin Invest 117(7):1782-93. [PubMed: 17607355]  [MGI Ref ID J:124190]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           MGL375

Colony Maintenance

Breeding & Husbandry	While maintaining a live colony, these mice are bred as heterozygotes. Mice homozygous for the mutation are not viable. Of note, mice on a C57BL/6 background have a brown coat color which is believed to be a result of the Becn1 mutation on melanogenesis.
Mating System	Wild-type x Heterozygote         (Female x Male)   12-DEC-12
	Heterozygote x Wild-type         (Female x Male)   12-DEC-12

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

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.

See Terms of Use tab for General Terms and Conditions

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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