Overview

Also Known As: PAI-1^-

These plasminogen activator inhibitor-1 deficient mice may be useful for studying the role of fibrosis and fibrinolysis in amyloid plaque deposition (Alzheimer's disease), hyperphagia, obesity, injury and muscular dystrophy.

Donating Investigator

Dr. Peter Carmeliet, University of Leuven

Genetic overview

Genetic Background	Generation
000664 C57BL/6J

Serpine1^tm1Mlg

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Serpine1	serine (or cysteine) peptidase inhibitor, clade E, member 1

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Research Applications

Cancer Research
Internal/Organ Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

Mice homozygous for this plasminogen activator inhibitor-1 null allele (PAI-1-) are viable and fertile with normal development. Compared to wildtype mice, pulmonary clot lysis is increased in the heterozygote and further increased in the homozygote. Endotoxin induced venous thrombosis is decreased compared to wildtype mice. Thus, disruption of the PAI-1 (Serpine1) gene induces a mild hyperfibrinolytic state. Hemostasis is normal in homozygous mutants.

Development

The plasminogen activator inhibitor-1 (PAI-1 or Serpine1) targeted null mutation was made in the laboratories of Dr. Richard Mulligan (Whitehead Institute for Biomedical Sciences) and of Dr. Peter Carmellet (University of Leuven). A targeting vector was used which resulted in the neomycin-resistant gene replacing all coding sequences. The Serpine1 gene was isolated from a BALB/c genomic library and targeting was done in D3 ES cells.

Control Suggestions

000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Carmeliet P; Kieckens L; Schoonjans L; Ream B; van Nuffelen A; Prendergast G; Cole M; Bronson R; Collen D; Mulligan RC. 1993. Plasminogen activator inhibitor-1 gene-deficient mice. I. Generation by homologous recombination and characterization. J Clin Invest 92(6):2746-55PubMed: 8254028 MGI: J:39819

View All References

Genetics

Serpine1^tm1Mlg

Allele Symbol: Serpine1^tm1Mlg

Allele Name	targeted mutation 1, Richard C Mulligan
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	targeted mutation 1, Richard C Mulligan; Serpine1^tm1Mlg
Gene Symbol and Name	Serpine1, serine (or cysteine) peptidase inhibitor, clade E, member 1
Gene Synonym(s)	Planh1; PAI; PAI-1; PAI1; PLANH1; plasminogen activator inhibitor, type I; PAI1A; Planh; RATPAI1A; Pai1aa; Pai1; Planh1
Strain of Origin	129S2/SvPas
Chromosome	5
Molecular Note	A PGK-neomycin resistance cassette replaced all of the Serpine1 coding sequence and part of the promoter region including the transcription initiation site. Northern blot analysis did not detect Serpine1 mRNA in endotoxin-treated homozygous mutant liver. Neither untreated nor endotoxin-treated homozygous mutant kidney produced detectable SERPINE1 immunoreactivity. A monoclonal antibody based immunofunctional assay did not detect protein levels in plasma of endotoxin-treated homozygous mutant mice.
Mutations Made By	Dr. Peter Carmeliet, University of Leuven

Disease/Phenotype

Disease Terms

Research Areas By Genotype

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

Genotype: Serpine1^tm1Mlg related

Cancer Research
- Defects in Cell Adhesion Molecules
Internal/Organ Research
- Wound Healing
  - enhanced

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Serpine1^tm1Mlg/Serpine1^tm1Mlg
involves: 129S2/SvPas * C57BL/6

adipose tissue phenotype

abnormal epididymal fat pad morphology
- after 12 weeks on a high fat diet, epididymal fat pad was only 25% of wild-type

decreased subcutaneous adipose tissue amount
- subcutaneous white fat pad mass was also reduced

homeostasis/metabolism phenotype

abnormal energy expenditure
- increased after 12 weeks on a high fat diet

abnormal enzyme/coenzyme activity
- after 8 hours, myeloperoxidase (MPO) activity is higher in mutants in hind limb homogenates than in wild-type

abnormal interleukin level
- local Il6 levels in injured tissue at 8 hours post-injection are lower than in controls

decreased circulating interleukin-6 level
- plasma levels are markedly reduced at 8 hours after turpentine injection

decreased liver triglyceride level
- lower levels after 12 weeks on a high fat diet

decreased triglyceride level
- lower levels in both skeletal muscle and liver after 12 weeks on a high fat diet

enhanced wound healing
- dermal incisions healed more rapidly than normal
- thickened epidermal layer found within newly healed wounds

increased body temperature
- increased on a high fat diet

increased oxygen consumption
- after 12 weeks on a high fat diet, oxygen consumption is increased

increased urine protein level
- an earlier enhancement of protein urea

immune system phenotype

abnormal acute inflammation
- C3 peak levels at day 3 are higher than in wild-type
- Normal - haptoglobin levels do not differ from wild-type at any time after turpentine injection
- in mutants after turpentine injection, serum amyloid P and C3 are significantly lower at 24 hours compared to wild-type and display a delayed peak at 3 days after injection

abnormal interleukin level
- local Il6 levels in injured tissue at 8 hours post-injection are lower than in controls

decreased circulating interleukin-6 level
- plasma levels are markedly reduced at 8 hours after turpentine injection

glomerulonephritis
- higher incidence of fibrin positive crescents
- increased infiltration of injury with CD4+ T cells
- increased mortality
- increased thrombin production

increased acute inflammation
- after turpentine injection to hind limb to induce tissue injury, 8 week-old mutants show significantly more local tissue injury compared to controls
- treatment resulted in local abscess formation and neutrophilic granulocyte infiltration encapsulated by macrophages and fibroblasts

increased granulocyte number
- relative to controls following turpentine injection

respiratory system inflammation
- fibrin content of lungs reduced generally
- inflammation induced fibrosis in the lung occurs at a much slower rate
- survival is better

cardiovascular system phenotype

abnormal blood circulation
- injury response in carotid arteries is reduced although cell proliferation in the adventitia is increased
- no fibrin present in the injured vessel walls

decreased angiogenesis
- neovascularization in general is reduced

integument phenotype

decreased subcutaneous adipose tissue amount
- subcutaneous white fat pad mass was also reduced

liver/biliary system phenotype

decreased liver triglyceride level
- lower levels after 12 weeks on a high fat diet

mammalian phenotype

hematopoietic system phenotype
- Normal - bleeding time was normal

immune system phenotype
- Normal - chemokine levels in injured tissue are similar between mutants and controls, peaking at 1-3 days

neoplasm
- Normal - after injection of melanoma cells, number of primary pulmonary metastases post-injection, or tumor burdens initiated by injections of increasing doses of cells do not significantly differ from wild-type controls
- Normal - no significant differences are observed compared to controls in terms of primary tumor size of footpad tumors induced by foot pad injection with tumor cells at 10, 17, or 21 days post-injection
- Normal - survival times after foot pad tumor removal are not significantly different among Serpine1-deficient, Serpine1-overexpressing transgenic, or wild-type mice

renal/urinary system phenotype

glomerular crescent
- higher incidence of fibrin positive crescents

glomerulonephritis
- higher incidence of fibrin positive crescents
- increased infiltration of injury with CD4+ T cells
- increased mortality
- increased thrombin production

increased urine protein level
- an earlier enhancement of protein urea

respiratory system phenotype

abnormal lung morphology
- collagen content
- lung fibrin deposition following bleomycin treatment is almost undetectable compared to treated wild-type mice
- no significant bleomycin-induced increase in lung collagen content is detected at 3 weeks posttreatment whereas treated wild-type mice show a significant increase in lung collagen; heterozygous mice are intermediate between null and wild-type in terms of collagen content

respiratory system inflammation
- fibrin content of lungs reduced generally
- inflammation induced fibrosis in the lung occurs at a much slower rate
- survival is better

growth/size/body region phenotype

abnormal body weight
- less weight gain on a high fat diet than normal

decreased body weight
- at 2 weeks, mutants remain below initial body weight after turpentine injection-induced weight loss but wild-type mice recover and begin to gain weight around 6-7 days after injection

weight loss
- turpentine injection induces significant weight loss in mutants and wild-type mice in initial 2 days; however, after 2 days, wild-type animals start to recover body weight whereas mutants do not

hematopoietic system phenotype

increased granulocyte number
- relative to controls following turpentine injection

Genotype: Serpine1^tm1Mlg/Serpine1^tm1Mlg
involves: 129S2/SvPas * C57BL/6 * C57BLKS/J

homeostasis/metabolism phenotype

decreased circulating cholesterol level
- mean levels are significantly lower than in wild-type controls and STZ-treated mutants

hyperglycemia
- in streptozotocin-treated (STZ) mice (to induce diabetes), serum glucose is significantly increased compared to untreated mutant or wild-type controls

increased blood urea nitrogen level
- STZ-treated mutants show elevated BUN levels compared to untreated mice, but levels are comparable to STZ-treated wild-type

mammalian phenotype

homeostasis/metabolism phenotype
- Normal - mice do not develop significant albuminuria after 6 months of streptozotocin (STZ) -induced diabetes

renal/urinary system phenotype

abnormal kidney morphology
- total kidney collagen in STZ-treated mice increases only 8% compared to 40% in treated wild-type

abnormal renal glomerulus morphology
- ed 64% relative to untreated wild-type mice
- glomerular extracellular matrix (ECM) area is greater than in wild-type controls; however, when expressed as fractional glomerular ECM area, little difference is observed between any genotype
- glomerular extracellular matrix (ECM) area is significantly higher compared to controls; after 6 months of STZ-induced diabetes, ECM area is decreased 15% compared to Serpine1 single deficient mice while in STZ-treated wild-type mice, ECM area is increased 64% relative to untreated wild-type mice

Genotype: Serpine1^tm1Mlg/Serpine1^tm1Mlg
involves: 129S2/SvPas

homeostasis/metabolism phenotype

decreased sensitivity to xenobiotic induced morbidity/mortality
- in mice treated with LPS

immune system phenotype

decreased susceptibility to endotoxin shock
- LPS-treated mice exhibit increased survival compared with wild-type mice

mortality/aging

decreased sensitivity to xenobiotic induced morbidity/mortality
- in mice treated with LPS

The following phenotype relates to a compound genotype created using this strain

Genotype: Serpine1^tm1Mlg/Serpine1^tm1Mlg
B6.129S2-Serpine1/J

cardiovascular system phenotype

cardiac fibrosis
- older mutants develop cardiac fibrosis, however fibrosis is not seen in the liver, spleen, lungs or kidneys and do not develop small vessel disease

heart inflammation
- older mutants exhibit significantly more macrophages in the heart

increased angiogenesis
- aortic vessel explants show increased capillary sprouting in both collagen lattices and Matrigel

liver/biliary system phenotype

liver fibrosis
- 3 weeks after bile duct ligation (BDL), hepatic fibrosis is reduced 18-26% compared to wild-type; hepatic collagen content is similar to sham-operated wild-type

mammalian phenotype

liver/biliary system phenotype
- Normal - stellate cell activation, TGFbeta-1 and collagen synthesis are similar in mutants and controls before and after bile duct ligation

mortality/aging

increased sensitivity to induced morbidity/mortality
- following infection with live Streptococcus pneumoniae, S. pneumoniae wild-type lysate, and S. pneumoniae pneumolysin (PLY), mice begin to die earlier and are all dead by 5 days post-infection
- following infection with S. pneumoniae strain ATCC 6303 (a more virulent strain), mortality is increased (10% survival compared to 45% in wild-type mice)

homeostasis/metabolism phenotype

abnormal enzyme/coenzyme activity
- 3 weeks after BDL, pro-MMP-9 and MMP-9 activities in liver homogenates from mutants are increased significantly compared to wild-type controls
- 3 weeks after BDL, urokinase plasminogen activator (uPA) and plasmin activity are not increased in mutants but tissue-type plasminogen activator (tPA) activity is significantly increased relative to wild-type

immune system phenotype

heart inflammation
- older mutants exhibit significantly more macrophages in the heart

increased susceptibility to bacterial infection
- following infection with S. pneumoniae strain ATCC 6303 (a more virulent strain), mortality is increased (10% survival compared to 45% in wild-type mice)
- following infection with S. pneumoniae, acute lung injury and alveolar hemorrhage is enhanced
- following infection with live Streptococcus pneumoniae, S. pneumoniae wild-type lysate, and S. pneumoniae pneumolysin (PLY), mice begin to die earlier and are all dead by 5 days post-infection

References

Carmeliet P; Kieckens L; Schoonjans L; Ream B; van Nuffelen A; Prendergast G; Cole M; Bronson R; Collen D; Mulligan RC. 1993. Plasminogen activator inhibitor-1 gene-deficient mice. I. Generation by homologous recombination and characterization. J Clin Invest 92(6):2746-55PubMed: 8254028 MGI: J:39819

Additional References

Carmeliet P; Stassen JM; Schoonjans L; Ream B; van den Oord JJ; De Mol M; Mulligan RC; Collen D. 1993. Plasminogen activator inhibitor-1 gene-deficient mice. II. Effects on hemostasis, thrombosis, and thrombolysis. J Clin Invest 92(6):2756-60PubMed: 8254029 MGI: J:67715
Chan JC; Duszczyszyn DA; Castellino FJ; Ploplis VA. 2001. Accelerated skin wound healing in plasminogen activator inhibitor-1-deficient mice. Am J Pathol 159(5):1681-8PubMed: 11696429 MGI: J:72394
Ma LJ; Mao SL; Taylor KL; Kanjanabuch T; Guan Y; Zhang Y; Brown NJ; Swift LL; McGuinness OP; Wasserman DH; Vaughan DE; Fogo AB. 2004. Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1. Diabetes 53(2):336-46PubMed: 14747283 MGI: J:87982
Hattori N; Mizuno S; Yoshida Y; Chin K; Mishima M; Sisson TH; Simon RH; Nakamura T; Miyake M. 2004. The plasminogen activation system reduces fibrosis in the lung by a hepatocyte growth factor-dependent mechanism. Am J Pathol 164(3):1091-8PubMed: 14982862 MGI: J:88462

Additional - Serpine1^tm1Mlg related

Technical Support

Contact Technical Support

Genotyping Protocols
- MELT: Serpine1^tm1Mlg
- Genotyping resources and troubleshooting
Mating System
- Homozygote x Homozygote
Appearance
- black
  Related Genotype: a/a
Citation
When using the PAI-1^- mouse strain in a publication, please cite the originating article(s) and include JAX stock #002507 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

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Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service	Genotype	Price
	Heterozygous for Serpine1<tm1Mlg>

We will fulfill your order by providing at least two carriers for each strain ordered. The total number, sex, and genotypes provided will vary, although typically 8 or more animals are provided. Please check genotypes which will be recovered. While the genotypes of all animals produced will be communicated to you prior to scheduling shipment, the genotypes of animals provided may not reflect the mating scheme and genotypes described in the strain description. Animals are typically ready to ship in 11-14 weeks. If a second recovery is required to produce the minimum number of animals, then delivery time would increase to approximately 25 weeks. If we fail to produce animals of the correct genotype, you will not be charged. We cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

Cryorecovery to establish a Dedicated Supply for greater quantities of mice. Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation.

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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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Also Known As: PAI-1-

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Serpine1tm1Mlg

Allele Symbol: Serpine1tm1Mlg

Disease Terms

Research Areas By Genotype

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

Genotype: Serpine1tm1Mlg related

Mammalian Phenotype Terms by Genotype

Genotype: Serpine1tm1Mlg/Serpine1tm1Mlginvolves: 129S2/SvPas * C57BL/6

adipose tissue phenotype

homeostasis/metabolism phenotype

immune system phenotype

cardiovascular system phenotype

integument phenotype

liver/biliary system phenotype

mammalian phenotype

renal/urinary system phenotype

respiratory system phenotype

growth/size/body region phenotype

hematopoietic system phenotype

Genotype: Serpine1tm1Mlg/Serpine1tm1Mlginvolves: 129S2/SvPas * C57BL/6 * C57BLKS/J

homeostasis/metabolism phenotype

mammalian phenotype

renal/urinary system phenotype

Genotype: Serpine1tm1Mlg/Serpine1tm1Mlginvolves: 129S2/SvPas

homeostasis/metabolism phenotype

immune system phenotype

mortality/aging

Genotype: Serpine1tm1Mlg/Serpine1tm1MlgB6.129S2-Serpine1/J

cardiovascular system phenotype

liver/biliary system phenotype

mammalian phenotype

mortality/aging

homeostasis/metabolism phenotype

immune system phenotype

References

Additional References

Additional - Serpine1tm1Mlg related

Genotyping Protocols

Mating System

Appearance

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms of Use

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Also Known As: PAI-1^-

Serpine1^tm1Mlg

Allele Symbol: Serpine1^tm1Mlg

Genotype: Serpine1^tm1Mlg related

Genotype: Serpine1^tm1Mlg/Serpine1^tm1Mlg
involves: 129S2/SvPas * C57BL/6

Genotype: Serpine1^tm1Mlg/Serpine1^tm1Mlg
involves: 129S2/SvPas * C57BL/6 * C57BLKS/J

Genotype: Serpine1^tm1Mlg/Serpine1^tm1Mlg
involves: 129S2/SvPas

Genotype: Serpine1^tm1Mlg/Serpine1^tm1Mlg
B6.129S2-Serpine1/J

Additional - Serpine1^tm1Mlg related