Description

Strain Information

Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse Generation N?+1F9pN1   Donating Investigator Frederick Alt,   Children's Hospital

Appearance
white-bellied agouti
Related Genotype: A^w/?

black
Related Genotype: a/a

Description
Mice homozygous for the Btk^tm1Wk targeted mutation are viable and fertile. Homozygous mutant mice show defects in B-cell maturation and activation. This strain has the same phenotype as the spontaneous X-linked immune deficiency mutation (CBA/CaHN-Btk^xid/J; Stock No. 001011). See Inbred Strain listing.

Development
Exons 13 and 14 of the gene, encoding the last 20 amino acids of the SH2 domain, and the first two exons of the kinase domain were deleted and replaced with neomycin. This deletion also disrupted the open reading frame and introduced a stop codon. No immunoreactive protein was detected in homozygous targeted mice.

Control Information

	Control
	101045 B6129SF2/J	(approximate)
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Btk

001011

CBA/CaHN-Btkxid/J

View Strains carrying other alleles of Btk     (1 strain)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

Bruton Agammaglobulinemia Tyrosine Kinase; BTK - Models with phenotypic similarity to human disease where etiologies involve orthologs.1

1 Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Btk^tm1Wk/Btk^tm1Wk

        involves: 129S4/SvJae * C57BL/6

• hematopoietic system phenotype
• abnormal B cell differentiation (MGI Ref ID J:28968)
  • partial arrest of B cell development
• abnormal B cell activation (MGI Ref ID J:28968)
  • defective B cell activation after immunization with T-independent type II antigens
• increased pro-B cell number (MGI Ref ID J:28968)
  • increased numbers of pro-B cells
• decreased mature B cell number (MGI Ref ID J:28968)
  • decreased numbers of mature B cells
• immune system phenotype
• abnormal B cell differentiation (MGI Ref ID J:28968)
  • partial arrest of B cell development
• abnormal B cell activation (MGI Ref ID J:28968)
  • defective B cell activation after immunization with T-independent type II antigens
• increased pro-B cell number (MGI Ref ID J:28968)
  • increased numbers of pro-B cells
• decreased IgG3 level (MGI Ref ID J:28968)
  • decreased serum IgG3 concentration
• decreased IgM level (MGI Ref ID J:28968)
  • decreased serum IgM concentration
• decreased mature B cell number (MGI Ref ID J:28968)
  • decreased numbers of mature B cells

View Research Applications

Research Applications

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

Btk^tm1Wk related

Hematological Research
Immunological Defects
Mast Cell Deficiency

Immunology and Inflammation Research
Immunodeficiency (B cell deficiency)
Inflammation

Mouse/Human Gene Homologs
Bruton agammaglobulinemia tyrosine kinase

Research Tools
Apoptosis Research
Cancer Research (B cell deficiency)
Immunology and Inflammation Research (B cell deficiency)

Genes & Alleles

Gene & Allele Information

Allele Symbol		Btktm1Wk
Allele Name		targeted mutation 1, Wasif Kahn
Allele Type		Targeted (knock-out)
Common Name(s)		Btk-; Btk-kin-/GL; BtkM;
Mutation Made By		Wasif Khan,   Children's Hospital
Strain of Origin		129S4/SvJae
ES Cell Line Name		J1
ES Cell Line Strain		129S4/SvJae
Gene Symbol and Name		Btk, Bruton agammaglobulinemia tyrosine kinase
Chromosome		X
Gene Common Name(s)		AGMX1; AI528679; AT; ATK; BPK; Bruton's tyrosine kinase; IMD1; MGC126261; MGC126262; PSCTK1; X-linked immune deficiency; XLA; expressed sequence AI528679; xid;
Molecular Note		A genomic fragment containing exons 13 and 14 was replaced with a neomycin resistance cassette. These sequences encode the beginning of the kinase domain. [MGI Ref ID J:28968]

Genotyping

Genotyping Information

Genotyping Protocols

Btk^tm1Wk, STD PCR, vers. 2

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Khan WN; Sideras P; Rosen FS; Alt FW. 1995. The role of Bruton's tyrosine kinase in B-cell development and function in mice and man. Ann N Y Acad Sci 764:27-38. [PubMed: 7486535]  [MGI Ref ID J:109912]

Additional References

Merchant M; Longnecker R. 2001. LMP2A survival and developmental signals are transmitted through Btk-dependent and Btk-independent pathways. Virology 291(1):46-54. [PubMed: 11878875]  [MGI Ref ID J:74306]

Btk^tm1Wk related

Atkinson BT; Ellmeier W; Watson SP. 2003. Tec regulates platelet activation by GPVI in the absence of Btk. Blood 102(10):3592-9. [PubMed: 12842985]  [MGI Ref ID J:86448]

Colombo MJ; Alugupalli KR. 2008. Complement Factor H-Binding Protein, a Putative Virulence Determinant of Borrelia hermsii, Is an Antigenic Target for Protective B1b Lymphocytes. J Immunol 180(7):4858-64. [PubMed: 18354209]  [MGI Ref ID J:133379]

Contreras CM; Halcomb KE; Randle L; Hinman RM; Gutierrez T; Clarke SH; Satterthwaite AB. 2007. Btk regulates multiple stages in the development and survival of B-1 cells. Mol Immunol 44(10):2719-28. [PubMed: 17207856]  [MGI Ref ID J:118704]

Ellmeier W; Jung S; Sunshine MJ; Hatam F; Xu Y; Baltimore D; Mano H; Littman DR. 2000. Severe B cell deficiency in mice lacking the tec kinase family members tec and Btk J Exp Med 192(11):1611-24. [PubMed: 11104803]  [MGI Ref ID J:66080]

Forssell J; Sideras P; Eriksson C; Malm-Erjefalt M; Rydell-Tormanen K; Ericsson PO; Erjefalt JS. 2005. Interleukin-2-inducible T cell kinase regulates mast cell degranulation and acute allergic responses. Am J Respir Cell Mol Biol 32(6):511-20. [PubMed: 15778496]  [MGI Ref ID J:110944]

Guo S; Wahl MI; Witte ON. 2006. Mutational analysis of the SH2-kinase linker region of Bruton's tyrosine kinase defines alternative modes of regulation for cytoplasmic tyrosine kinase families. Int Immunol 18(1):79-87. [PubMed: 16291652]  [MGI Ref ID J:104167]

Habib T; Park H; Tsang M; de Alboran IM; Nicks A; Wilson L; Knoepfler PS; Andrews S; Rawlings DJ; Eisenman RN; Iritani BM. 2007. Myc stimulates B lymphocyte differentiation and amplifies calcium signaling. J Cell Biol 179(4):717-31. [PubMed: 17998397]  [MGI Ref ID J:135554]

Halcomb KE; Contreras CM; Hinman RM; Coursey TG; Wright HL; Satterthwaite AB. 2007. Btk and phospholipase Cgamma2 can function independently during B cell development. Eur J Immunol 37(4):1033-42. [PubMed: 17372989]  [MGI Ref ID J:120843]

Halcomb KE; Musuka S; Gutierrez T; Wright HL; Satterthwaite AB. 2008. Btk regulates localization, in vivo activation, and class switching of anti-DNA B cells. Mol Immunol :. [PubMed: 18849077]  [MGI Ref ID J:141113]

Hasan M; Lopez-Herrera G; Blomberg KE; Lindvall JM; Berglof A; Smith CI; Vargas L. 2008. Defective Toll-like receptor 9-mediated cytokine production in B cells from Bruton's tyrosine kinase-deficient mice. Immunology 123(2):239-49. [PubMed: 17725607]  [MGI Ref ID J:134805]

Ho LH; Uehara T; Chen CC; Kubagawa H; Cooper MD. 1999. Constitutive tyrosine phosphorylation of the inhibitory paired Ig-like receptor PIR-B. Proc Natl Acad Sci U S A 96(26):15086-90. [PubMed: 10611342]  [MGI Ref ID J:119839]

Iwaki S; Tkaczyk C; Satterthwaite AB; Halcomb K; Beaven MA; Metcalfe DD; Gilfillan AM. 2005. Btk plays a crucial role in the amplification of Fc epsilonRI-mediated mast cell activation by kit. J Biol Chem 280(48):40261-70. [PubMed: 16176929]  [MGI Ref ID J:132405]

Jumaa H; Mitterer M; Reth M; Nielsen PJ. 2001. The absence of SLP65 and Btk blocks B cell development at the preB cell receptor-positive stage. Eur J Immunol 31(7):2164-9. [PubMed: 11449370]  [MGI Ref ID J:70406]

Karlsson MC; Guinamard R; Bolland S; Sankala M; Steinman RM; Ravetch JV. 2003. Macrophages control the retention and trafficking of B lymphocytes in the splenic marginal zone. J Exp Med 198(2):333-40. [PubMed: 12874264]  [MGI Ref ID J:119256]

Kawakami Y; Inagaki N; Salek-Ardakani S; Kitaura J; Tanaka H; Nagao K; Kawakami Y; Xiao W; Nagai H; Croft M; Kawakami T. 2006. Regulation of dendritic cell maturation and function by Bruton's tyrosine kinase via IL-10 and Stat3. Proc Natl Acad Sci U S A 103(1):153-8. [PubMed: 16371463]  [MGI Ref ID J:104554]

Kawakami Y; Kitaura J; Hartman SE; Lowell CA; Siraganian RP; Kawakami T. 2000. Regulation of protein kinase CbetaI by two protein-tyrosine kinases, Btk and Syk. Proc Natl Acad Sci U S A 97(13):7423-8. [PubMed: 10852954]  [MGI Ref ID J:126402]

Kawakami Y; Kitaura J; Satterthwaite AB; Kato RM; Asai K; Hartman SE; Maeda-Yamamoto M; Lowell CA; Rawlings DJ; Witte ON; Kawakami T. 2000. Redundant and opposing functions of two tyrosine kinases, Btk and Lyn, in mast cell activation. J Immunol 165(3):1210-9. [PubMed: 10903718]  [MGI Ref ID J:120482]

Khan WN; Alt FW; Gerstein RM; Malynn BA; Larsson I; Rathbun G; Davidson L; Muller S; Kantor AB; Herzenberg LA; Rosen FS; Sideras P. 1995. Defective B cell development and function in Btk-deficient mice. Immunity 3(3):283-99. [PubMed: 7552994]  [MGI Ref ID J:28968]

Khan WN; Nilsson A; Mizoguchi E; Castigli E; Forsell J; Bhan AK; Geha R; Sideras P; Alt FW. 1997. Impaired B cell maturation in mice lacking Bruton's tyrosine kinase (Btk) and CD40. Int Immunol 9(3):395-405. [PubMed: 9088978]  [MGI Ref ID J:82298]

Kitaura J; Eto K; Kinoshita T; Kawakami Y; Leitges M; Lowell CA; Kawakami T. 2005. Regulation of highly cytokinergic IgE-induced mast cell adhesion by Src, Syk, Tec, and protein kinase C family kinases. J Immunol 174(8):4495-504. [PubMed: 15814670]  [MGI Ref ID J:98164]

Kneidinger M; Schmidt U; Rix U; Gleixner KV; Vales A; Baumgartner C; Lupinek C; Weghofer M; Bennett KL; Herrmann H; Schebesta A; Thomas WR; Vrtala S; Valenta R; Lee FY; Ellmeier W; Superti-Furga G; Valent P. 2008. The effects of dasatinib on IgE receptor-dependent activation and histamine release in human basophils. Blood 111(6):3097-107. [PubMed: 18180381]  [MGI Ref ID J:132738]

Lee KG; Xu S; Wong ET; Tergaonkar V; Lam KP. 2008. Bruton's tyrosine kinase separately regulates NFkappaB p65RelA activation and cytokine interleukin (IL)-10/IL-12 production in TLR9-stimulated B Cells. J Biol Chem 283(17):11189-98. [PubMed: 18276597]  [MGI Ref ID J:136576]

Lindvall JM; Blomberg KE; Berglof A; Yang Q; Smith CI; Islam TC. 2004. Gene expression profile of B cells from Xid mice and Btk knockout mice. Eur J Immunol 34(7):1981-91. [PubMed: 15214046]  [MGI Ref ID J:115493]

Mecklenbrauker I; Kalled SL; Leitges M; Mackay F; Tarakhovsky A. 2004. Regulation of B-cell survival by BAFF-dependent PKCdelta-mediated nuclear signalling. Nature 431(7007):456-61. [PubMed: 15361883]  [MGI Ref ID J:92667]

Melcher M; Unger B; Schmidt U; Rajantie IA; Alitalo K; Ellmeier W. 2008. Essential roles for the Tec family kinases Tec and Btk in M-CSF receptor signaling pathways that regulate macrophage survival. J Immunol 180(12):8048-56. [PubMed: 18523268]  [MGI Ref ID J:137240]

Merchant M; Longnecker R. 2001. LMP2A survival and developmental signals are transmitted through Btk-dependent and Btk-independent pathways. Virology 291(1):46-54. [PubMed: 11878875]  [MGI Ref ID J:74306]

Petro JB; Rahman SM; Ballard DW; Khan WN. 2000. Bruton's tyrosine kinase is required for activation of IkappaB kinase and nuclear factor kappaB in response to B cell receptor engagement. J Exp Med 191(10):1745-54. [PubMed: 10811867]  [MGI Ref ID J:110720]

Pisitkun P; Deane JA; Difilippantonio MJ; Tarasenko T; Satterthwaite AB; Bolland S. 2006. Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science 312(5780):1669-72. [PubMed: 16709748]  [MGI Ref ID J:109758]

Satterthwaite AB; Cheroutre H; Khan WN; Sideras P; Witte ON. 1997. Btk dosage determines sensitivity to B cell antigen receptor cross-linking. Proc Natl Acad Sci U S A 94(24):13152-7. [PubMed: 9371815]  [MGI Ref ID J:108696]

Satterthwaite AB; Lowell CA; Khan WN; Sideras P; Alt FW; Witte ON. 1998. Independent and opposing roles for Btk and lyn in B and myeloid signaling pathways. J Exp Med 188(5):833-44. [PubMed: 9730885]  [MGI Ref ID J:50288]

Satterthwaite AB; Willis F; Kanchanastit P; Fruman D; Cantley LC; Helgason CD; Humphries RK; Lowell CA; Simon M; Leitges M; Tarakhovsky A; Tedder TF; Lesche R; Wu H; Witte ON. 2000. A sensitized genetic system for the analysis of murine B lymphocyte signal transduction pathways dependent on Bruton's tyrosine kinase. Proc Natl Acad Sci U S A 97(12):6687-92. [PubMed: 10829070]  [MGI Ref ID J:62717]

Schmidt NW; Mayo LD; Donner DB; Kaplan MH. 2006. p53 regulates Btk-dependent B cell proliferation but not differentiation. J Leukoc Biol 79(4):852-9. [PubMed: 16461747]  [MGI Ref ID J:107548]

Schmidt NW; Thieu VT; Mann BA; Ahyi AN; Kaplan MH. 2006. Bruton's tyrosine kinase is required for TLR-induced IL-10 production. J Immunol 177(10):7203-10. [PubMed: 17082638]  [MGI Ref ID J:140621]

Shimomura Y; Ogawa A; Kawada M; Sugimoto K; Mizoguchi E; Shi HN; Pillai S; Bhan AK; Mizoguchi A. 2008. A unique B2 B cell subset in the intestine. J Exp Med 205(6):1343-55. [PubMed: 18519649]  [MGI Ref ID J:137039]

Shinohara M; Koga T; Okamoto K; Sakaguchi S; Arai K; Yasuda H; Takai T; Kodama T; Morio T; Geha RS; Kitamura D; Kurosaki T; Ellmeier W; Takayanagi H. 2008. Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals. Cell 132(5):794-806. [PubMed: 18329366]  [MGI Ref ID J:135537]

Soriani A; Moran B; de Virgilio M; Kawakami T; Altman A; Lowell C; Eto K; Shattil SJ. 2006. A role for PKCtheta in outside-in alpha(IIb)beta3 signaling. J Thromb Haemost 4(3):648-55. [PubMed: 16460447]  [MGI Ref ID J:135793]

Suzuki H; Matsuda S; Terauchi Y; Fujiwara M; Ohteki T; Asano T; Behrens TW; Kouro T; Takatsu K; Kadowaki T; Koyasu S. 2003. PI3K and Btk differentially regulate B cell antigen receptor-mediated signal transduction. Nat Immunol 4(3):280-6. [PubMed: 12563258]  [MGI Ref ID J:96704]

Webb CF; Yamashita Y; Ayers N; Evetts S; Paulin Y; Conley ME; Smith EA. 2000. The transcription factor Bright associates with Bruton's tyrosine kinase, the defective protein in immunodeficiency disease. J Immunol 165(12):6956-65. [PubMed: 11120822]  [MGI Ref ID J:118397]

Whyburn LR; Halcomb KE; Contreras CM; Lowell CA; Witte ON; Satterthwaite AB. 2003. Reduced dosage of Bruton's tyrosine kinase uncouples B cell hyperresponsiveness from autoimmunity in lyn-/- mice. J Immunol 171(4):1850-8. [PubMed: 12902486]  [MGI Ref ID J:84810]

Yu PW; Tabuchi RS; Kato RM; Astrakhan A; Humblet-Baron S; Kipp K; Chae K; Ellmeier W; Witte ON; Rawlings DJ. 2004. Sustained correction of B-cell development and function in a murine model of X-linked agammaglobulinemia (XLA) using retroviral-mediated gene transfer. Blood 104(5):1281-90. [PubMed: 15142874]  [MGI Ref ID J:92704]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information.

Supply Notes

Cryopreserved Embryos This strain is also available as cryopreserved embryos from our Repository. Orders for cryopreserved embryos are supplied subject to a signed agreement that must be returned to the Customer Service Department after order placement. Experienced technicians at The Jackson Laboratory have recovered frozen embryos of this strain successfully. We will provide you enough embryos to perform two embryo transfers. The Jackson Laboratory does not guarantee successful recovery at your facility. For complete information on purchasing embryos from our repository, please visit our Cryopreserved Embryos web page. Cryorecovery - Standard. The recovery process begins when a signed agreement form is returned to the Customer Service Department after order placement. Although results vary by strain, at least two males and two females (two pairs) will be provided, typically within 15 weeks of our receipt of the signed agreement form. If the first recovery attempt is unsuccessful or only one pair is recovered, a second recovery will be done, extending the delivery time to approximately 25 weeks. At least one member of each pair will be of known genotype and will carry the mutation if it is a mutant strain. Please note that pairs may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation of the strain. Mating schemes are sometimes modified for successful cryopreservation. Price represents a repository maintenance fee, which includes the cost of recovery of the strain from the cryopreservation resource and the periodic replacement of the frozen embryos used for recovery. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. One to two pairs will be recovered to establish a Dedicated Supply of mice. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 or 1-207-288-5845. This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	101045 B6129SF2/J	(approximate)
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

General Terms and Conditions

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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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phone:	207-288-6470
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