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 Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Species laboratory mouse Generation F?+3 Generation Definitions   Donating Investigator Nora Heisterkamp,   Childrens Hospital Los Angeles

Description
Mice that are homozygous null for the Bcr gene are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. No Bcr gene product (mRNA or protein) is detected. Homozygous null animals are more susceptible to lipopolysaccharide (LPS) -induced endotoxemia. Sublethal doses of LPS induce septic shock characterized by a pronounced, sustained neutrophilia and tissue damage to multiple organs. Tissue damage is mediated by neutrophils that exhibit an elevated superoxide production resulting in similarly elevated respiratory burst. Neutrophils obtained from null animals that have been activated in vitro with phorbol myristate actetate (PMA) show an almost 100% increase in respiratory burst over that seen in wildtype neutrophils.

Development
A targeting vector containing a neomycin resistance gene driven by the mouse phosphoglycerate kinase promoter was used to disrupt a portion of intron 1 and exon2 of the Bcr gene. The construct was electroporated into 129S2/SvPas-derived D3 embryonic stem (ES) cells. A herpes simplex virus thymidine kinase was used for negative selection. Correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting chimeric male animals were backcrossed to C57BL/6J females.

Control Information

	Control
	See control note:	The STOCK background of this strain is a mixture of C57BL/6 and 129S2 inbred strains, plus random-bred Black Swiss mice. Thus, the best physiological controls would be wildtype mice 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. Leukemia, Acute Lymphoblastic; ALL   (BCR) Leukemia, Chronic Myeloid; CML   (BCR)

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.

Bcr^tm1Hkp/Bcr^tm1Hkp

        involves: 129S2/SvPas

• immune system phenotype
• abnormal neutrophil physiology
  • following activation with phorbol myristate acetate (PMA) or PMA and N-formyl-Met-Leu-Phe, neutrophils exhibit a 100% increase in respiratory burst compared to similarly treated wild-type mice   (MGI Ref ID J:23804)
  • neutrophils are more easily primed and activated compared to wild-type cells   (MGI Ref ID J:23804)
  • neutrophils exhibit spontaneous activation unlike wild-type cells   (MGI Ref ID J:23804)
• increased leukocyte cell number
  • in the kidney and liver 6 hours after LPS-exposure unlike similarly treated wild-type mice   (MGI Ref ID J:23804)
• • increased neutrophil cell number
    • 6 hours after LPS-exposure, mice exhibit a 2- to 3- fold increase in circulating neutrophils that is sustained and more pronounced than in similarly treated wild-type mice   (MGI Ref ID J:23804)
• increased susceptibility to endotoxin shock
  • mice exposed to LPS develop septic shock lasting at least 4 days accompanied by weight loss and intestinal edema before onset of recovery unlike similarly treated wild-type mice that recover within 24 hours of exposure   (MGI Ref ID J:23804)
  • unlike in wild-type mice, LPS exposure leads to extensive damage in multiple organs including the ileum, kidney, and liver   (MGI Ref ID J:23804)
  • however, removal of neutrophils using cyclophosphamide treatment restores normal response to LPS   (MGI Ref ID J:23804)
  • LPS-exposed mice exhibit increased plasma lactate dehydrogenase, aspartate and alanine aminotransferase, and blood nitrogen urea compared to similarly treated wild-type mice   (MGI Ref ID J:23804)
• sepsis
  • mice exposed to LPS develop septic shock lasting at least 4 days before recovery unlike similarly treated wild-type mice   (MGI Ref ID J:23804)
• homeostasis/metabolism phenotype
• increased blood urea nitrogen level
  • following LPS exposure   (MGI Ref ID J:23804)
• increased circulating alanine transaminase level
  • following LPS exposure   (MGI Ref ID J:23804)
• increased circulating aspartate transaminase level
  • following LPS exposure   (MGI Ref ID J:23804)
• increased lactate dehydrogenase level
  • following LPS exposure   (MGI Ref ID J:23804)
• intestinal edema
  • following LPS exposure   (MGI Ref ID J:23804)
• renal/urinary system phenotype
• abnormal proximal convoluted tubule morphology
  • LPS-treated mice exhibit extensive vacuolization of proximal convoluted tubules unlike similarly treated wild-type mice   (MGI Ref ID J:23804)
• abnormal renal glomerulus morphology
  • LPS-treated mice exhibit glomerular collapse as early as 6 hours post-exposure unlike similarly treated wild-type mice   (MGI Ref ID J:23804)
• renal necrosis
  • LPS-treated mice exhibit cortical necrosis unlike similarly treated wild-type mice   (MGI Ref ID J:23804)
• liver/biliary system phenotype
• abnormal liver parenchyma morphology
  • 72 hours after LPS-exposure, mice exhibit fatty vacuolization in the liver parenchyma unlike similarly treated wild-type mice   (MGI Ref ID J:23804)
• digestive/alimentary phenotype
• abnormal ileum morphology
  • unlike in wild-type mice, LPS-treated mice exhibit the presence of debris and mucus plugs in the intestinal lumen and in between microvilli indicating necrosis of mucosal epithelial cells at 24 hours post-exposure   (MGI Ref ID J:23804)
• intestinal edema
  • following LPS exposure   (MGI Ref ID J:23804)
• growth/size phenotype
• weight loss
  • following LPS exposure   (MGI Ref ID J:23804)
• hematopoietic system phenotype
• abnormal hematopoiesis
  • 72 hours after LPS-exposure, hematopoiesis shifts to granulopoiesis unlike in similarly treated wild-type mice   (MGI Ref ID J:23804)
• • increased leukocyte cell number
    • in the kidney and liver 6 hours after LPS-exposure unlike similarly treated wild-type mice   (MGI Ref ID J:23804)
  • • increased neutrophil cell number
      • 6 hours after LPS-exposure, mice exhibit a 2- to 3- fold increase in circulating neutrophils that is sustained and more pronounced than in similarly treated wild-type mice   (MGI Ref ID J:23804)

View Research Applications

Research Applications

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

Bcr^tm1Hkp related

Immunology, Inflammation and Autoimmunity Research
Inflammation
      Neutrophil defects

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Bcrtm1Hkp
Allele Name		targeted mutation 1, Nora Heisterkamp
Allele Type		Targeted (knock-out)
Mutation Made By		Nora Heisterkamp,   Childrens Hospital Los Angeles
Strain of Origin		129S2/SvPas
ES Cell Line Name		D3
ES Cell Line Strain		129S2/SvPas
Gene Symbol and Name		Bcr, breakpoint cluster region
Chromosome		10
Gene Common Name(s)		5133400C09Rik; AI561783; AI853148; ALL; BCR1; CML; D22S11; D22S662; PHL; RIKEN cDNA 5133400C09 gene; expressed sequence AI561783; expressed sequence AI853148; mKIAA3017;
Molecular Note		Exon 2 was partially replaced by insertion of a neomycin resistance expression cassette. Northern blot analysis with an exon 1 specific probe demonstrated that the transcript was not expressed in brain of homozygous mice, and western blot analysis on brain extracts showed that no protein was produced in homozygotes. [MGI Ref ID J:23804]

Genotyping

Genotyping Information

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Voncken JW; van Schaick H; Kaartinen V; Deemer K; Coates T; Landing B; Pattengale P; Dorseuil O; Bokoch GM; Groffen J; Heisterkamp N. 1995. Increased neutrophil respiratory burst in bcr-null mutants. Cell 80(5):719-28. [PubMed: 7889565]  [MGI Ref ID J:23804]

Additional References

Voncken JW; Kaartinen V; Groffen J; Heisterkamp N. 1998. Bcr/Abl associated leukemogenesis in bcr null mutant mice. Oncogene 16(15):2029-32. [PubMed: 9591787]  [MGI Ref ID J:47417]

Bcr^tm1Hkp related

Cho YJ; Cunnick JM; Yi SJ; Kaartinen V; Groffen J; Heisterkamp N. 2007. Abr and Bcr, two homologous Rac GTPase-activating proteins, control multiple cellular functions of murine macrophages. Mol Cell Biol 27(3):899-911. [PubMed: 17116687]  [MGI Ref ID J:118168]

Cunnick JM; Schmidhuber S; Chen G; Yu M; Yi SJ; Cho YJ; Kaartinen V; Minoo P; Warburton D; Groffen J; Heisterkamp N. 2009. Bcr and Abr cooperate in negatively regulating acute inflammatory responses. Mol Cell Biol 29(21):5742-50. [PubMed: 19703997]  [MGI Ref ID J:153997]

Kaartinen V; Gonzalez-Gomez I; Voncken JW; Haataja L; Faure E; Nagy A; Groffen J; Heisterkamp N. 2001. Abnormal function of astroglia lacking Abr and Bcr RacGAPs. Development 128(21):4217-27. [PubMed: 11684658]  [MGI Ref ID J:72425]

Kaartinen V; Nagy A; Gonzalez-Gomez I; Groffen J; Heisterkamp N. 2002. Vestibular dysgenesis in mice lacking Abr and Bcr Cdc42/RacGAPs. Dev Dyn 223(4):517-25. [PubMed: 11921339]  [MGI Ref ID J:108010]

Ngo VN; Korner H; Gunn MD; Schmidt KN; Riminton DS; Cooper MD; Browning JL; Sedgwick JD; Cyster JG. 1999. Lymphotoxin alpha/beta and tumor necrosis factor are required for stromal cell expression of homing chemokines in B and T cell areas of the spleen. J Exp Med 189(2):403-12. [PubMed: 9892622]  [MGI Ref ID J:52941]

Oh D; Han S; Seo J; Lee JR; Choi J; Groffen J; Kim K; Cho YS; Choi HS; Shin H; Woo J; Won H; Park SK; Kim SY; Jo J; Whitcomb DJ; Cho K; Kim H; Bae YC; Heisterkamp N; Choi SY; Kim E. 2010. Regulation of synaptic Rac1 activity, long-term potentiation maintenance, and learning and memory by BCR and ABR Rac GTPase-activating proteins. J Neurosci 30(42):14134-44. [PubMed: 20962234]  [MGI Ref ID J:165475]

Voncken JW; Baram TZ; Gonzales-Gomez I I; van Schaick H; Shih JC; Chen K; Groffen J; Heisterkamp N. 1998. Abnormal stress response and increased fighting behavior in mice lacking the bcr gene product. Int J Mol Med 2(5):577-583. [PubMed: 9858655]  [MGI Ref ID J:51186]

Voncken JW; Kaartinen V; Groffen J; Heisterkamp N. 1998. Bcr/Abl associated leukemogenesis in bcr null mutant mice. Oncogene 16(15):2029-32. [PubMed: 9591787]  [MGI Ref ID J:47417]

Wang Y; Wang J; Sun Y; Wu Q; Fu YX. 2001. Complementary effects of TNF and lymphotoxin on the formation of germinal center and follicular dendritic cells J Immunol 166(1):330-7. [PubMed: 11123309]  [MGI Ref ID J:66397]

Wu Q; Wang Y; Wang J; Hedgeman EO; Browning JL; Fu YX. 1999. The requirement of membrane lymphotoxin for the presence of dendritic cells in lymphoid tissues. J Exp Med 190(5):629-38. [PubMed: 10477548]  [MGI Ref ID J:110887]

Yu M; Gong D; Lim M; Arutyunyan A; Groffen J; Heisterkamp N. 2012. Lack of bcr and abr promotes hypoxia-induced pulmonary hypertension in mice. PLoS One 7(11):e49756. [PubMed: 23152932]  [MGI Ref ID J:195022]

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	This strain originated on a B6;129S2 background. It was crossed with a Black Swiss mouse for an unknown number of generations before being made homozygous. The donating investigator recommends that males not be housed together.

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:	The STOCK background of this strain is a mixture of C57BL/6 and 129S2 inbred strains, plus random-bred Black Swiss mice. Thus, the best physiological controls would be wildtype mice from the colony.
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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