Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse Generation N17+2F1N1   Donating Investigator David Williams,   Indiana University

Description
Mice that are homozygous for the targeted mutation are viable, fertile, and normal in size but exhibit phagocytic immunodeficiency. No endogenous gene product (mRNA or protein) was detected by Northern blot analysis, RT-PCR or Western blot analysis. The Rac proteins are a subclass of the Rho family of GTPases, and are involved in actin cytoskeletal organization in cell movement, cell proliferation, kinase signaling pathways, and in superoxide production in phagocytic cells. Neutrophils and mast cells derived from homozygous mice display abnormal actin-based functions: cytoskeleton remodeling ability, adhesion, migration, degranulation, and phagocytosis. Diminished superoxide production in response to some agonists, and reduced total number of leukocytes and neutrophils in peritoneal exudate is observed. As result of functional deficiencies in neutrophil and mast cell populations, these mutant mice are more vulnerable to invasive infection. Slowed growth of mast cells, accompanying reduction in mast cell number and a significant decrease in growth factor-dependent survival was found to be due to increased cell apoptosis. These mutant mice may be useful in studies of phagocytic immunodeficiency, cellular inflammatory responses, hematopoietic cell regulation, and B cell development and signaling.

Development
A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was used to disrupt exon 1 of the Rac2 gene. The construct was electroporated into 129S6/SvEv derived CCE.1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric animals were crossed to C57BL/6 mice.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls

Additional Web Information

Congenic Nomenclature

Phenotype

Phenotype Information

View Research Applications

Research Applications

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

Rac2^tm1Mddw related

Apoptosis Research
Extracellular Modulators

Cancer Research
Genes Regulating Growth and Proliferation

Developmental Biology Research
Defects in Cell Adhesion Molecules

Hematological Research
Immunological Defects (B and T cell deficiency)
Mast Cell Deficiency

Immunology and Inflammation Research
Growth Factors/Receptors/Cytokines
Immunodeficiency (B cell deficiency)
Immunodeficiency Associated with Other Defects
Inflammation (B and T cell deficiency)
Inflammation (Neutrophil defects)
Intracellular Signaling Molecules
Lymphoid Tissue Defects (B and T cell deficiency)
T Cell Receptor Signaling Defects (B and T cell deficiency)

Research Tools
Apoptosis Research
Cancer Research (B cell deficiency)
Cancer Research (T cell deficiency)
Cancer Research (production of B cells and antibodies)

Currently there is no phenotype information for this strain.

Genes & Alleles

Gene & Allele Information

Allele Symbol		Rac2tm1Mddw
Allele Name		targeted mutation 1, Mary C Dinauer and David A Williams
Allele Type		Targeted (knock-out)
Common Name(s)		Rac2tm1Daw; rac2-;
Mutation Made By		David Williams,   Indiana University
Strain of Origin		129S/SvEv-Gpi1
ES Cell Line Name		CCE/EK.CCE
ES Cell Line Strain		129S/SvEv-Gpi1
Gene Symbol and Name		Rac2, RAS-related C3 botulinum substrate 2
Chromosome		15
Gene Common Name(s)		AI323801; AI452260; EN-7; Gx; HSPC022; MGC105983; expressed sequence AI323801; expressed sequence AI452260;
General Note		Homozygous mutant animals appear normal and are fertile, but show modest leukocytosis due to increased circulating neutrophils. These mutant neutrophils, however, have an impaired actin cytoskeleton, including: decreased ability to generate F-actin and polymerize actin in response to physiological stimuli, perturbations in directed cell movement, defects in cell orientation in response to chemoattractants, under developed lamellipodia, and impaired endothelial substrate interaction. Unactivated neutrophils from Rac2 mutants show reduced superoxide production, but activated neutrophils are normal, suggesting that Rac2 plays an important (but replaceable) function in superoxide production. This impairment might be compensated for by Rac1. Rac2 mutants are also more susceptible to the opportunistic pathogen Aspergillus fumigatus. This may be a consequence of low neutrophil recruitment to sites of inflammation (even though there is an increased circulating neutrophil population), overall impaired neutrophil function, or a combination of both (J:53362).
Molecular Note		A neomycin resistance cassette replaced a genomic fragment containing exon 1, which encodes the translational initiation site and part of the GTP-binding domain. Northern blot and RT-PCR analysis demonstrated that no transcripts were detectable in totalRNA derived from neutrophils or lymphocytes in homozygous mice. Western blot analysis confirmed an absence of protein produced from this allele in peritoneal exudate cells from homozygous mice. [MGI Ref ID J:53362]

Genotyping

Genotyping Information

Genotyping Protocols

Rac2^tm1Mddw, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Roberts AW; Kim C; Zhen L; Lowe JB; Kapur R; Petryniak B; Spaetti A; Pollock JD; Borneo JB; Bradford GB; Atkinson SJ; Dinauer MC; Williams DA. 1999. Deficiency of the hematopoietic cell-specific Rho family GTPase Rac2 is characterized by abnormalities in neutrophil function and host defense. Immunity 10(2):183-96. [PubMed: 10072071]  [MGI Ref ID J:53362]

Additional References

Cancelas JA; Lee AW; Prabhakar R; Stringer KF; Zheng Y; Williams DA. 2005. Rac GTPases differentially integrate signals regulating hematopoietic stem cell localization. Nat Med 11(8):886-91. [PubMed: 16025125]  [MGI Ref ID J:110380]

Croker BA; Tarlinton DM; Cluse LA; Tuxen AJ; Light A; Yang FC; Williams DA; Roberts AW. 2002. The Rac2 guanosine triphosphatase regulates B lymphocyte antigen receptor responses and chemotaxis and is required for establishment of B-1a and marginal zone B lymphocytes. J Immunol 168(7):3376-86. [PubMed: 11907095]  [MGI Ref ID J:75581]

Filippi MD; Harris CE; Meller J; Gu Y; Zheng Y; Williams DA. 2004. Localization of Rac2 via the C terminus and aspartic acid 150 specifies superoxide generation, actin polarity and chemotaxis in neutrophils. Nat Immunol 5(7):744-51. [PubMed: 15170212]  [MGI Ref ID J:91126]

Gu Y; Filippi MD; Cancelas JA; Siefring JE; Williams EP; Jasti AC; Harris CE; Lee AW; Prabhakar R; Atkinson SJ; Kwiatkowski DJ; Williams DA. 2003. Hematopoietic cell regulation by Rac1 and Rac2 guanosine triphosphatases. Science 302(5644):445-9. [PubMed: 14564009]  [MGI Ref ID J:86814]

Rac2^tm1Mddw related

Abdel-Latif D; Steward M; Macdonald DL; Francis GA; Dinauer MC; Lacy P. 2004. Rac2 is critical for neutrophil primary granule exocytosis. Blood 104(3):832-9. [PubMed: 15073033]  [MGI Ref ID J:92258]

Arana E; Vehlow A; Harwood NE; Vigorito E; Henderson R; Turner M; Tybulewicz VL; Batista FD. 2008. Activation of the small GTPase Rac2 via the B cell receptor regulates B cell adhesion and immunological-synapse formation. Immunity 28(1):88-99. [PubMed: 18191593]  [MGI Ref ID J:131150]

Azim AC; Cao H; Gao X; Joo M; Malik AB; van Breemen RB; Sadikot RT; Park G; Christman JW. 2007. Regulation of cyclooxygenase-2 expression by small GTPase Rac2 in bone marrow macrophages. Am J Physiol Lung Cell Mol Physiol 293(3):L668-73. [PubMed: 17575012]  [MGI Ref ID J:128040]

Cancelas JA; Jansen M; Williams DA. 2006. The role of chemokine activation of Rac GTPases in hematopoietic stem cell marrow homing, retention, and peripheral mobilization. Exp Hematol 34(8):976-85. [PubMed: 16863904]  [MGI Ref ID J:111908]

Croker BA; Handman E; Hayball JD; Baldwin TM; Voigt V; Cluse LA; Yang FC; Williams DA; Roberts AW. 2002. Rac2-deficient mice display perturbed T-cell distribution and chemotaxis, but only minor abnormalities in T(H)1 responses. Immunol Cell Biol 80(3):231-40. [PubMed: 12067410]  [MGI Ref ID J:77489]

Croker BA; Tarlinton DM; Cluse LA; Tuxen AJ; Light A; Yang FC; Williams DA; Roberts AW. 2002. The Rac2 guanosine triphosphatase regulates B lymphocyte antigen receptor responses and chemotaxis and is required for establishment of B-1a and marginal zone B lymphocytes. J Immunol 168(7):3376-86. [PubMed: 11907095]  [MGI Ref ID J:75581]

Fulkerson PC; Zhu H; Williams DA; Zimmermann N; Rothenberg ME. 2005. CXCL9 inhibits eosinophil responses by a CCR3- and Rac2-dependent mechanism. Blood 106(2):436-43. [PubMed: 15802529]  [MGI Ref ID J:107462]

Gomez JC; Soltys J; Okano K; Dinauer MC; Doerschuk CM. 2008. The role of Rac2 in regulating neutrophil production in the bone marrow and circulating neutrophil counts. Am J Pathol 173(2):507-17. [PubMed: 18583316]  [MGI Ref ID J:138295]

Gu Y; Filippi MD; Cancelas JA; Siefring JE; Williams EP; Jasti AC; Harris CE; Lee AW; Prabhakar R; Atkinson SJ; Kwiatkowski DJ; Williams DA. 2003. Hematopoietic cell regulation by Rac1 and Rac2 guanosine triphosphatases. Science 302(5644):445-9. [PubMed: 14564009]  [MGI Ref ID J:86814]

Guo F; Cancelas JA; Hildeman D; Williams DA; Zheng Y. 2008. Rac GTPase isoforms Rac1 and Rac2 play a redundant and crucial role in T-cell development. Blood 112(5):1767-75. [PubMed: 18579797]  [MGI Ref ID J:138889]

Hall AB; Gakidis MA; Glogauer M; Wilsbacher JL; Gao S; Swat W; Brugge JS. 2006. Requirements for Vav guanine nucleotide exchange factors and Rho GTPases in FcgammaR- and complement-mediated phagocytosis. Immunity 24(3):305-16. [PubMed: 16546099]  [MGI Ref ID J:113323]

Ingram DA; Hiatt K; King AJ; Fisher L; Shivakumar R; Derstine C; Wenning MJ; Diaz B; Travers JB; Hood A; Marshall M; Williams DA; Clapp DW. 2001. Hyperactivation of p21(ras) and the hematopoietic-specific Rho GTPase, Rac2, cooperate to alter the proliferation of neurofibromin-deficient mast cells in vivo and in vitro. J Exp Med 194(1):57-69. [PubMed: 11435472]  [MGI Ref ID J:71331]

Kalfa TA; Pushkaran S; Mohandas N; Hartwig JH; Fowler VM; Johnson JF; Joiner CH; Williams DA; Zheng Y. 2006. Rac GTPases regulate the morphology and deformability of the erythrocyte cytoskeleton. Blood 108(12):3637-45. [PubMed: 16882712]  [MGI Ref ID J:140447]

Kim C; Dinauer MC. 2006. Impaired NADPH oxidase activity in Rac2-deficient murine neutrophils does not result from defective translocation of p47phox and p67phox and can be rescued by exogenous arachidonic acid. J Leukoc Biol 79(1):223-34. [PubMed: 16275890]  [MGI Ref ID J:104739]

Kim C; Dinauer MC. 2001. Rac2 is an essential regulator of neutrophil nicotinamide adenine dinucleotide phosphate oxidase activation in response to specific signaling pathways. J Immunol 166(2):1223-32. [PubMed: 11145705]  [MGI Ref ID J:66852]

Koh AL; Sun CX; Zhu F; Glogauer M. 2005. The role of Rac1 and Rac2 in bacterial killing. Cell Immunol 235(2):92-7. [PubMed: 16157315]  [MGI Ref ID J:107943]

Li B; Yu H; Zheng W; Voll R; Na S; Roberts AW; Williams DA; Davis RJ; Ghosh S; Flavell RA. 2000. Role of the guanosine triphosphatase Rac2 in T helper 1 cell differentiation. Science 288(5474):2219-22. [PubMed: 10864872]  [MGI Ref ID J:63080]

Li S; Yamauchi A; Marchal CC; Molitoris JK; Quilliam LA; Dinauer MC. 2002. Chemoattractant-stimulated rac activation in wild-type and rac2-deficient murine neutrophils: preferential activation of rac2 and rac2 gene dosage effect on neutrophil functions. J Immunol 169(9):5043-51. [PubMed: 12391220]  [MGI Ref ID J:79793]

McCarty OJ; Larson MK; Auger JM; Kalia N; Atkinson BT; Pearce AC; Ruf S; Henderson RB; Tybulewicz VL; Machesky LM; Watson SP. 2005. Rac1 is essential for platelet lamellipodia formation and aggregate stability under flow. J Biol Chem 280(47):39474-84. [PubMed: 16195235]  [MGI Ref ID J:104107]

Ojha N; Roy S; He G; Biswas S; Velayutham M; Khanna S; Kuppusamy P; Zweier JL; Sen CK. 2008. Assessment of wound-site redox environment and the significance of Rac2 in cutaneous healing. Free Radic Biol Med 44(4):682-91. [PubMed: 18068132]  [MGI Ref ID J:131305]

Pestonjamasp KN; Forster C; Sun C; Gardiner EM; Bohl B; Weiner O; Bokoch GM; Glogauer M. 2006. Rac1 links leading edge and uropod events through Rho and myosin activation during chemotaxis. Blood 108(8):2814-20. [PubMed: 16809619]  [MGI Ref ID J:139459]

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]

Sun CX; Downey GP; Zhu F; Koh AL; Thang H; Glogauer M. 2004. Rac1 is the small GTPase responsible for regulating the neutrophil chemotaxis compass. Blood 104(12):3758-65. [PubMed: 15308574]  [MGI Ref ID J:94828]

Tan BL; Yazicioglu MN; Ingram D; McCarthy J; Borneo J; Williams DA; Kapur R. 2003. Genetic evidence for convergence of c-Kit- and alpha4 integrin-mediated signals on class IA PI-3kinase and the Rac pathway in regulating integrin-directed migration in mast cells. Blood 101(12):4725-32. [PubMed: 12560232]  [MGI Ref ID J:109998]

Thomas EK; Cancelas JA; Chae HD; Cox AD; Keller PJ; Perrotti D; Neviani P; Druker BJ; Setchell KD; Zheng Y; Harris CE; Williams DA. 2007. Rac guanosine triphosphatases represent integrating molecular therapeutic targets for BCR-ABL-induced myeloproliferative disease. Cancer Cell 12(5):467-78. [PubMed: 17996650]  [MGI Ref ID J:127321]

Utomo A; Cullere X; Glogauer M; Swat W; Mayadas TN. 2006. Vav proteins in neutrophils are required for FcgammaR-mediated signaling to Rac GTPases and nicotinamide adenine dinucleotide phosphate oxidase component p40(phox). J Immunol 177(9):6388-97. [PubMed: 17056570]  [MGI Ref ID J:140509]

Utomo A; Hirahashi J; Mekala D; Asano K; Glogauer M; Cullere X; Mayadas TN. 2008. Requirement for Vav proteins in post-recruitment neutrophil cytotoxicity in IgG but not complement C3-dependent injury. J Immunol 180(9):6279-87. [PubMed: 18424751]  [MGI Ref ID J:134524]

Walmsley MJ; Ooi SK; Reynolds LF; Smith SH; Ruf S; Mathiot A; Vanes L; Williams DA; Cancro MP; Tybulewicz VL. 2003. Critical roles for Rac1 and Rac2 GTPases in B cell development and signaling. Science 302(5644):459-62. [PubMed: 14564011]  [MGI Ref ID J:86765]

Wang QQ; Li H; Oliver T; Glogauer M; Guo J; He YW. 2008. Integrin beta1 regulates phagosome maturation in macrophages through Rac expression. J Immunol 180(4):2419-28. [PubMed: 18250451]  [MGI Ref ID J:131992]

Wheeler AP; Wells CM; Smith SD; Vega FM; Henderson RB; Tybulewicz VL; Ridley AJ. 2006. Rac1 and Rac2 regulate macrophage morphology but are not essential for migration. J Cell Sci 119(Pt 13):2749-57. [PubMed: 16772332]  [MGI Ref ID J:110344]

Yamauchi A; Marchal CC; Molitoris J; Pech N; Knaus U; Towe J; Atkinson SJ; Dinauer MC. 2005. Rac GTPase isoform-specific regulation of NADPH oxidase and chemotaxis in murine neutrophils in vivo. Role of the C-terminal polybasic domain. J Biol Chem 280(2):953-64. [PubMed: 15504745]  [MGI Ref ID J:96141]

Yan J; Chen S; Zhang Y; Li X; Li Y; Wu X; Yuan J; Robling AG; Karpur R; Chan RJ; Yang FC. 2008. Rac1 mediates the osteoclast gains-in-function induced by haploinsufficiency of Nf1. Hum Mol Genet 17(7):936-48. [PubMed: 18089636]  [MGI Ref ID J:132466]

Yu H; Leitenberg D; Li B; Flavell RA. 2001. Deficiency of small GTPase Rac2 affects T cell activation. J Exp Med 194(7):915-26. [PubMed: 11581314]  [MGI Ref ID J:119437]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	This strain originated on a B6;129 background and has been backcrossed for at least 17 generations (11/01) on the C57BL/6 background. Homozygous mice must be maintained under specific pathogen-free conditions.
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

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
	Wild-type from the colony
	000664 C57BL/6J
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'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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Fax: 207.288.6150
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phone:	207-288-6470
fax:	207-288-6655

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