Description

Strain Information

Former Names B6.129X1-Ela2tm1Sds/J    (Changed: 15-MAY-09 ) Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Mating System Homozygote x Homozygote         (Female x Male)   25-SEP-07 Species laboratory mouse Generation N10F?+10 (09-DEC-09) Generation Definitions   Donating Investigator Steven Shapiro,   University of Pittsburgh

Description
Homozygous mice are viable, fertile and phenotypically normal in the absence of inflammatory stress. Homozygotes do not express the targeted gene in bone marrow myeloid cells. Homozygous mice have increased susceptibility to sepsis, morbidity, and mortality following intraperitoneal injection of Gram-negative (e.g. (K. pneumoniae and E. coli), but not Gram-positive (e.g. (S. aureus), bacteria. Despite this, mutant mice are not at increased risk to spontaneous infection. Although neutrophil, T cell, and macrophage migration/recruitment to the site of infection is unaffected in homozygous mutant mice, neutrophils show impaired bactericidal activity. Further, homozygous mice treated with a broad-spectrum inflammatory stimulus (zymosan) have impaired leukocyte firm adhesion and transmigration as well as reduced pro-inflammatory cytokine production. Upon exposure to cigarette smoke, homozygous mice are protected from the accumulation of neutrophils and macrophages in the lungs, as well as the development of airspace enlargement. These mutant mice may be useful in studies of immunity and immunology, including host defense against Gram-negative bacteria, granulocyte/neutrophil function, sepsis, and cigarette smoke-induced emphysema.

Development
A targeting vector containing a neomycin phosphotransferase cDNA driven by the phosphoglycerate kinase promoter (PGK-neo) was used to replace exon 2 (which contains the histidine residue of the catalytic triad) of the endogenous gene. The construct was electroporated into 129X1/SvJ-derived RW4 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting chimeric animals crossed to 129X1/SvJ mice, and the strain was maintained on this background for an unknown number of generations. The donating investigator reports that mutant mice were then mated to "C57BL/6 mice from Charles River" (C57BL/6NCrl) (see SNP note below) for at least 10 generations before arrival at The Jackson Laboratory. Upon arrival, male and female mice were bred together.

A 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at The Jackson Laboratory Repository. While the 27 markers throughout the genome suggested a C57BL/6 genetic background, at least 2 of 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating. These data suggest the mice sent to The Jackson Laboratory Repository were on a mixed C57BL/6J ; C57BL/6N genetic background.

Control Information

	Control
	000664 C57BL/6J	(approximate)
	005304 C57BL/6NJ
Considerations for Choosing Controls

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Elane^tm1Sds/Elane^tm1Sds

        B6.129X1-Elane^tm1Sds

• homeostasis/metabolism phenotype
• decreased physiological sensitivity to xenobiotic
  • mice exhibit 59% protection from emphysema induced by a 6 month cigarette smoke exposure   (MGI Ref ID J:86599)
  • following a 6 month exposure to cigarette smoke, mice exhibit fewer neutrophils and 60% less macrophages in bronchoalveolar lavage samples compared to wild-type mice   (MGI Ref ID J:86599)

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

Elane^tm1Sds/Elane^tm1Sds

        129X1/SvJ-Elane^tm1Sds

• mortality/aging
• decreased susceptibility to bacterial infection induced morbidity/mortality
  • mice are less susceptible to death induced by Gram positive Staphylococcus aureus infection compared to wild-type mice   (MGI Ref ID J:47420)
• increased susceptibility to bacterial infection induced morbidity/mortality
  • at 16 hours following infection with Gram negative Klebsiella pneumoniae, 50% of mice are dead unlike wild-type mice that do not display mortality due to infection at 16 hours   (MGI Ref ID J:47420)
  • at 48 hours following infection with Klebsiella pneumoniae, all mice are dead unlike wild-type mice that display 50% mortality   (MGI Ref ID J:47420)
• immune system phenotype
• abnormal neutrophil physiology
  • despite normal neutrophil recruitment, recognition and binding, neutrophils fail to degrade phagocytosed Klebsiella pneumoniae or Escherichia coli unlike in wild-type mice   (MGI Ref ID J:47420)
• decreased susceptibility to bacterial infection induced morbidity/mortality
  • mice are less susceptible to death induced by Gram positive Staphylococcus aureus infection compared to wild-type mice   (MGI Ref ID J:47420)
• increased susceptibility to bacterial infection
  • mice appear clinically worse than wild-type mice following infection with Gram negative Klebsiella pneumoniae or Escherichia coli   (MGI Ref ID J:47420)
  • when infected with Klebsiella pneumoniae, mice exhibit signs of severe infection including ruffled fur, hunched posture, impaired ambulation and diarrhea unlike wild-type mice   (MGI Ref ID J:47420)
  • despite normal neutrophil recruitment, recognition and binding, bacterial burden is greater than in wild-type mice following infection with Klebsiella pneumoniae   (MGI Ref ID J:47420)
• • increased susceptibility to bacterial infection induced morbidity/mortality
    • at 16 hours following infection with Gram negative Klebsiella pneumoniae, 50% of mice are dead unlike wild-type mice that do not display mortality due to infection at 16 hours   (MGI Ref ID J:47420)
    • at 48 hours following infection with Klebsiella pneumoniae, all mice are dead unlike wild-type mice that display 50% mortality   (MGI Ref ID J:47420)

Elane^tm1Sds/Elane^tm1Sds

        involves: 129X1/SvJ

• homeostasis/metabolism phenotype
• decreased physiological sensitivity to xenobiotic
  • unlike in wild-type mice, ONO-5046 has no inhibitory effects on IL-1beta-induced leukocyte transmigration   (MGI Ref ID J:124377)

Elane^tm1Sds/Elane^tm1Sds

        involves: 129X1/SvJ * C57BL/6

• immune system phenotype
• abnormal inflammatory response
  • following exposure to LPS then challenge with TNF at the same site to initiate a local Shwartman response, mice fail to exhibit hemorrhage or fibrin deposition, characteristic of thrombohemorrhagic vasculitis, unlike in wild-type mice despite normal neutrophil accumulation   (MGI Ref ID J:113463)

View Research Applications

Research Applications

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

Cancer Research
Growth Factors/Receptors/Cytokines

Cardiovascular Research
Vascular Defects
      defective leukocyte function

Hematological Research
Neutrophil Defects

Immunology and Inflammation Research
CD Antigens, Antigen Receptors, and Histocompatibility Markers
      genes regulating susceptibility to infectious disease and endotoxin
Growth Factors/Receptors/Cytokines
Immunodeficiency
      Neutrophil Defects
Inflammation
      Neutrophil defects

Internal/Organ Research
Lung Defects
      emphysema

Mouse/Human Gene Homologs
leukocyte adhesion deficiency, type I

Research Tools
Cancer Research
      Leukemia
Immunology and Inflammation Research
      genes regulating susceptibility to infectious disease and endotoxin

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Elanetm1Sds
Allele Name		targeted mutation 1, Steven D Shapiro
Allele Type		Targeted (knock-out)
Common Name(s)		NE-;
Mutation Made By		Steven Shapiro,   University of Pittsburgh
Strain of Origin		129X1/SvJ
ES Cell Line Name		RW-4
ES Cell Line Strain		129X1/SvJ
Gene Symbol and Name		Elane, elastase, neutrophil expressed
Chromosome		10
Gene Common Name(s)		ELA2; Ela2; F430011M15Rik; GE; HLE; HNE; NE; PMN-E; RIKEN cDNA F430011M15 gene; SCN1; elastase 2, neutrophil; neutrophil elastase;
Molecular Note		The insertion of a neomycin selection cassette replaced exon 2, which encodes the histidine residue of the catalytic triad. Northern blot analysis of total RNA obtained from bone marrow myeloid cells showed that transcript encoded by the targeted allele was absent. Reprobing of the blot showed that the expression of the closely linked proteinase 3 was unaffected by the targeting event. An absence of elastocytic activity derived from the targeted locus was determined via kappa-elastin zymography. [MGI Ref ID J:47420]

Genotyping

Genotyping Information

Genotyping Protocols

Ela2^tm1Sds, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Belaaouaj A; McCarthy R; Baumann M; Gao Z; Ley TJ; Abraham SN; Shapiro SD. 1998. Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis. Nat Med 4(5):615-8. [PubMed: 9585238]  [MGI Ref ID J:47420]

Additional References

Elane^tm1Sds related

Akk AM; Simmons PM; Chan HW; Agapov E; Holtzman MJ; Grayson MH; Pham CT. 2008. Dipeptidyl peptidase I-dependent neutrophil recruitment modulates the inflammatory response to sendai virus infection. J Immunol 180(5):3535-42. [PubMed: 18292580]  [MGI Ref ID J:131520]

Allport JR; Lim YC; Shipley JM; Senior RM; Shapiro SD; Matsuyoshi N; Vestweber D; Luscinskas FW. 2002. Neutrophils from MMP-9- or neutrophil elastase-deficient mice show no defect in transendothelial migration under flow in vitro. J Leukoc Biol 71(5):821-8. [PubMed: 11994507]  [MGI Ref ID J:76606]

Bergin DA; Greene CM; Sterchi EE; Kenna C; Geraghty P; Belaaouaj A; Taggart CC; O'Neill SJ; McElvaney NG. 2008. Activation of the epidermal growth factor receptor (EGFR) by a novel metalloprotease pathway. J Biol Chem 283(46):31736-44. [PubMed: 18772136]  [MGI Ref ID J:143128]

Edelstein C; Shapiro SD; Klezovitch O; Scanu AM. 1999. Macrophage metalloelastase, MMP-12, cleaves human apolipoprotein(a) in the linker region between kringles IV-4 and IV-5. Potential relevance to lipoprotein(a) biology. J Biol Chem 274(15):10019-23. [PubMed: 10187779]  [MGI Ref ID J:115221]

Fang H; Sun C; Xu L; Owen RJ; Auth RD; Snoy PJ; Frucht DM. 2010. Neutrophil elastase mediates pathogenic effects of anthrax lethal toxin in the murine intestinal tract. J Immunol 185(9):5463-7. [PubMed: 20921524]  [MGI Ref ID J:165180]

Grenda DS; Johnson SE; Mayer JR; McLemore ML; Benson KF; Horwitz M; Link DC. 2002. Mice expressing a neutrophil elastase mutation derived from patients with severe congenital neutropenia have normal granulopoiesis. Blood 100(9):3221-8. [PubMed: 12384420]  [MGI Ref ID J:131496]

Hirahashi J; Hishikawa K; Kaname S; Tsuboi N; Wang Y; Simon DI; Stavrakis G; Shimosawa T; Xiao L; Nagahama Y; Suzuki K; Fujita T; Mayadas TN. 2009. Mac-1 (CD11b/CD18) links inflammation and thrombosis after glomerular injury. Circulation 120(13):1255-65. [PubMed: 19752320]  [MGI Ref ID J:167501]

Hirahashi J; Mekala D; Van Ziffle J; Xiao L; Saffaripour S; Wagner DD; Shapiro SD; Lowell C; Mayadas TN. 2006. Mac-1 signaling via Src-family and Syk kinases results in elastase-dependent thrombohemorrhagic vasculopathy. Immunity 25(2):271-83. [PubMed: 16872848]  [MGI Ref ID J:113463]

Hirche TO; Atkinson JJ; Bahr S; Belaaouaj A. 2004. Deficiency in neutrophil elastase does not impair neutrophil recruitment to inflamed sites. Am J Respir Cell Mol Biol 30(4):576-84. [PubMed: 14565940]  [MGI Ref ID J:97295]

Hirche TO; Benabid R; Deslee G; Gangloff S; Achilefu S; Guenounou M; Lebargy F; Hancock RE; Belaaouaj A. 2008. Neutrophil elastase mediates innate host protection against Pseudomonas aeruginosa. J Immunol 181(7):4945-54. [PubMed: 18802098]  [MGI Ref ID J:142738]

Hirche TO; Crouch EC; Espinola M; Brokelman TJ; Mecham RP; DeSilva N; Cooley J; Remold-O'Donnell E; Belaaouaj A. 2004. Neutrophil serine proteinases inactivate surfactant protein D by cleaving within a conserved subregion of the carbohydrate recognition domain. J Biol Chem 279(26):27688-98. [PubMed: 15078883]  [MGI Ref ID J:123985]

Hirche TO; Gaut JP; Heinecke JW; Belaaouaj A. 2005. Myeloperoxidase plays critical roles in killing Klebsiella pneumoniae and inactivating neutrophil elastase: effects on host defense. J Immunol 174(3):1557-65. [PubMed: 15661916]  [MGI Ref ID J:96406]

Houghton AM; Rzymkiewicz DM; Ji H; Gregory AD; Egea EE; Metz HE; Stolz DB; Land SR; Marconcini LA; Kliment CR; Jenkins KM; Beaulieu KA; Mouded M; Frank SJ; Wong KK; Shapiro SD. 2010. Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth. Nat Med 16(2):219-23. [PubMed: 20081861]  [MGI Ref ID J:157079]

Kaynar AM; Houghton AM; Lum EH; Pitt BR; Shapiro SD. 2008. Neutrophil elastase is needed for neutrophil emigration into lungs in ventilator-induced lung injury. Am J Respir Cell Mol Biol 39(1):53-60. [PubMed: 18276796]  [MGI Ref ID J:151216]

Lane AA; Ley TJ. 2003. Neutrophil elastase cleaves PML-RARalpha and is important for the development of acute promyelocytic leukemia in mice. Cell 115(3):305-18. [PubMed: 14636558]  [MGI Ref ID J:86458]

Lane AA; Ley TJ. 2005. Neutrophil elastase is important for PML-retinoic acid receptor alpha activities in early myeloid cells. Mol Cell Biol 25(1):23-33. [PubMed: 15601827]  [MGI Ref ID J:95151]

Levesque JP; Liu F; Simmons PJ; Betsuyaku T; Senior RM; Pham C; Link DC. 2004. Characterization of hematopoietic progenitor mobilization in protease-deficient mice. Blood 104(1):65-72. [PubMed: 15010367]  [MGI Ref ID J:90920]

Liu Z; Zhou X; Shapiro SD; Shipley JM; Twining SS; Diaz LA; Senior RM; Werb Z. 2000. The serpin alpha1-proteinase inhibitor is a critical substrate for gelatinase B/MMP-9 in vivo. Cell 102(5):647-55. [PubMed: 11007483]  [MGI Ref ID J:64322]

Nanua S; Murakami M; Xia J; Grenda DS; Woloszynek J; Strand M; Link DC. 2011. Activation of the unfolded protein response is associated with impaired granulopoiesis in transgenic mice expressing mutant Elane. Blood 117(13):3539-47. [PubMed: 21285438]  [MGI Ref ID J:170501]

Papayannopoulos V; Metzler KD; Hakkim A; Zychlinsky A. 2010. Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J Cell Biol 191(3):677-91. [PubMed: 20974816]  [MGI Ref ID J:166722]

Raptis SZ; Shapiro SD; Simmons PM; Cheng AM; Pham CT. 2005. Serine protease cathepsin g regulates adhesion-dependent neutrophil effector functions by modulating integrin clustering. Immunity 22(6):679-91. [PubMed: 15963783]  [MGI Ref ID J:99112]

Shao B; Wahrenbrock MG; Yao L; David T; Coughlin SR; Xia L; Varki A; McEver RP. 2011. Carcinoma mucins trigger reciprocal activation of platelets and neutrophils in a murine model of Trousseau syndrome. Blood 118(15):4015-23. [PubMed: 21860019]  [MGI Ref ID J:178397]

Shapiro SD; Goldstein NM; Houghton AM; Kobayashi DK; Kelley D; Belaaouaj A. 2003. Neutrophil elastase contributes to cigarette smoke-induced emphysema in mice. Am J Pathol 163(6):2329-35. [PubMed: 14633606]  [MGI Ref ID J:86599]

Stowe AM; Adair-Kirk TL; Gonzales ER; Perez RS; Shah AR; Park TS; Gidday JM. 2009. Neutrophil elastase and neurovascular injury following focal stroke and reperfusion. Neurobiol Dis 35(1):82-90. [PubMed: 19393318]  [MGI Ref ID J:150458]

Wang S; Dangerfield JP; Young RE; Nourshargh S. 2005. PECAM-1, {alpha}6 integrins and neutrophil elastase cooperate in mediating neutrophil transmigration. J Cell Sci 118(Pt 9):2067-76. [PubMed: 15840647]  [MGI Ref ID J:98057]

Wang S; Voisin MB; Larbi KY; Dangerfield J; Scheiermann C; Tran M; Maxwell PH; Sorokin L; Nourshargh S. 2006. Venular basement membranes contain specific matrix protein low expression regions that act as exit points for emigrating neutrophils. J Exp Med 203(6):1519-32. [PubMed: 16754715]  [MGI Ref ID J:124377]

Young RE; Thompson RD; Larbi KY; La M; Roberts CE; Shapiro SD; Perretti M; Nourshargh S. 2004. Neutrophil elastase (NE)-deficient mice demonstrate a nonredundant role for NE in neutrophil migration, generation of proinflammatory mediators, and phagocytosis in response to zymosan particles in vivo. J Immunol 172(7):4493-502. [PubMed: 15034066]  [MGI Ref ID J:88722]

Zhang M; Liu N; Park SM; Wang Y; Byrne S; Murmann AE; Bahr S; Peter ME; Olson ST; Belaaouaj A; Ashton-Rickardt PG. 2007. Serine protease inhibitor 6-deficient mice have increased neutrophil immunity to Pseudomonas aeruginosa. J Immunol 179(7):4390-6. [PubMed: 17878334]  [MGI Ref ID J:152360]

Zhao M; Trimbeger ME; Li N; Diaz LA; Shapiro SD; Liu Z. 2006. Role of FcRs in animal model of autoimmune bullous pemphigoid. J Immunol 177(5):3398-405. [PubMed: 16920981]  [MGI Ref ID J:139536]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX11

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice are bred as homozygotes. While the publications indicate mutant mice are not at increased risk to spontaneous infection, The Jackson Laboratory maintains homozygous colonies in microisolator ventilation.
Mating System	Homozygote x Homozygote         (Female x Male)   25-SEP-07
Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls

General Supply Notes

• This strain is included in the Induced Mutant Resource Colony collection.
• Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	000664 C57BL/6J	(approximate)
	005304 C57BL/6NJ
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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