JAX Mouse Strain Datasheet - 002509

B6.129S2-Plau^tm1Mlg/J

Stock No:: 002509

Cryo Recovery

Overview

Homozygotes develop normally, have a normal life span, and are poor breeders. Pups often need fostering. Rectal prolapse of a non-infectious origin develops in 9% of homozygotes and/or extensive non-healing ulcerations occur at the eyelids and around the face. Small, focal fibrin deposits are occasionally seen in the intestines and in the sinusoids of the liver, and excessive fibrin deposits are seen in ulcerated skin or prolapsed rectum. Pulmonary clot lysis is comparable to that seen in normal wildtype siblings. Endotoxin induced venous thrombosis is increased over normal wildtype siblings. Fibrin dissolution by PLAU-deficient macrophages is greatly reduced but macrophage invasion into the peritoneal cavity after thioglycollate injection is unaffected. Homozygous knockout mice have increased levels of Abeta42 and Abeta40 in plasma. Brain Abeta levels are not significantly different than controls. In an attempt to offer alleles on well-characterized or multiple genetic backgrounds,...

Donating Investigator
Dr. Peter Carmeliet, University of Leuven
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Genetic overview

Genetic Background Generation

C57BL/6

Plau^tm1Mlg

Allele Type Gene Symbol Gene Name

Targeted (Null/Knockout) Plau plasminogen activator, urokinase
View Genetics

Research Applications

Hematological Research
Metabolism Research
Neurobiology Research

View All Research Applications

Base Price

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$2,595.00 Domestic price Cryo Recovery

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Genetic Background	Generation
C57BL/6

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Plau	plasminogen activator, urokinase

Details

Detailed Description

Homozygotes develop normally, have a normal life span, and are poor breeders. Pups often need fostering. Rectal prolapse of a non-infectious origin develops in 9% of homozygotes and/or extensive non-healing ulcerations occur at the eyelids and around the face. Small, focal fibrin deposits are occasionally seen in the intestines and in the sinusoids of the liver, and excessive fibrin deposits are seen in ulcerated skin or prolapsed rectum. Pulmonary clot lysis is comparable to that seen in normal wildtype siblings. Endotoxin induced venous thrombosis is increased over normal wildtype siblings. Fibrin dissolution by PLAU-deficient macrophages is greatly reduced but macrophage invasion into the peritoneal cavity after thioglycollate injection is unaffected. Homozygous knockout mice have increased levels of Abeta42 and Abeta40 in plasma. Brain Abeta levels are not significantly different than controls. In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. This is the case for the strain above. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.

Development

This targeted mutant was made in the laboratories of Dr. Richard Mulligan of the Whitehead Institute for Biomedical Sciences, Cambridge Massachusetts and of Dr. Peter Carmellet at the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium. A targeting vector was used which resulted in the neomycin-resistant gene (neo) replacing all but 23 amino acids of the coding sequence. Targeting was done in 129S2/SvPas-derived D3 ES cells.

Control Suggestions

Wild-type from the colony
000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References
Carmeliet P; Schoonjans L; Kieckens L; Ream B; Degen J; Bronson R; De Vos R; van den Oord JJ; Collen D; Mulligan RC. 1994. Physiological consequences of loss of plasminogen activator gene function in mice. Nature 368(6470):419-24. PubMed: 8133887 MGI: J:17427
View All References

Genetics

Plau^tm1Mlg

Allele Symbol: Plau^tm1Mlg

Allele Name targeted mutation 1, Richard C Mulligan

Allele Type Targeted (Null/Knockout)

Allele Synonym(s) UPA-; u-PA^-; uPA-

Gene Symbol and Name Plau, plasminogen activator, urokinase

Gene Synonym(s) ATF; BDPLT5; QPD; UPA; UPAM; URK; u-PA; uPA; urokinase-type plasminogen activator

Strain of Origin 129S2/SvPas

Chromosome 14

Molecular Note The gene was disrupted using neomycin resistance cassette. The vector replaced genomic sequences encompassing all but 23 amino acids of the coding sequence. Targeting was confirmed by the absence of gene specific mRNA and immunoreactivity.

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: Plau^tm1Mlg related
Hematological Research
Clotting Defects
Metabolism Research
Neurobiology Research
Alzheimer's Disease

Mammalian Phenotype Terms by Genotype

Genotype: Plau^tm1Mlg/Plau^tm1Mlg
B6.129S2-Plau^tm1Mlg
mortality/aging
premature death
only 5 of 8 mice survive for a year
(MGI Ref ID J:164542)
immune system phenotype
chronic inflammation
chronic inflammation is secondary to fibrin deposition
(MGI Ref ID J:164542)
increased inflammatory response
however, leukocyte accumulation in standard models of inflammation is normal
(MGI Ref ID J:164542)
in the liver and trachea
(MGI Ref ID J:164542)
liver inflammation
the number of inflammatory foci is increased compared to in wild-type mice
(MGI Ref ID J:164542)
trachea inflammation
all mice exhibit inflammation in the trachea
(MGI Ref ID J:164542)
liver/biliary system phenotype
decreased liver glycogen level
(MGI Ref ID J:164542)
liver fibrosis
2.5-fold more frequent in number compared with Plau^tm1.1Bug or Plaur^tm1Jld homozygotes
(MGI Ref ID J:164542)
liver inflammation
the number of inflammatory foci is increased compared to in wild-type mice
(MGI Ref ID J:164542)
homeostasis/metabolism phenotype
abnormal response to injury
following treatment with carbon tetrachloride, substantial areas of necrosis persist in the liver unlike in similarly treated wild-type mice
(MGI Ref ID J:164542)
however, skin wound healing is normal
(MGI Ref ID J:164542)
decreased liver glycogen level
(MGI Ref ID J:164542)
respiratory system phenotype
abnormal trachea morphology
all mice exhibit inflammation in the trachea with basement membrane hyperplasia and desquamation of the tracheal epithelium unlike in wild-type mice
(MGI Ref ID J:164542)
trachea fibrosis
mice exhibit fibrosis in the trachea unlike wild-type mice
(MGI Ref ID J:164542)
trachea inflammation
all mice exhibit inflammation in the trachea
(MGI Ref ID J:164542)
adipose tissue phenotype
decreased total body fat amount
(MGI Ref ID J:164542)
growth/size/body region phenotype
cachexia
some mice die before 1 year with a wasting syndrome
(MGI Ref ID J:164542)
Genotype: Plau^tm1Mlg/Plau^tm1Mlg
either: B6.Cg-Plau^tm1Mlg or (involves: Black Swiss * C57BL/6)
homeostasis/metabolism phenotype
reduced thrombolysis
in a model of pulmonary microembolism, wild-type mice are able to clear 125I-microemboli rapidly with complete lysis by 5 hours; in contrast, mutants remain unable to lyse pulmonary microemboli throughout the 5-hr experimental period
(MGI Ref ID J:64220)
in these mutants, impaired fibrinolysis can be rescued completely by providing urokinase exogenously
(MGI Ref ID J:64220)
The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain
Genotype: Plau^tm1Mlg/Plau^tm1Mlg
B6.Cg-Plau^tm1Mlg
neoplasm
abnormal tumor morphology
3 weeks after implantation of T241 fibrosarcoma cells, primary tumors from mutant mice appear to be better delineated and less hemorrhagic than tumors from wild-type mice
(MGI Ref ID J:65383)
also, tumors from mutant mice show an increase in collagen deposition at the periphery of the lesion, forming a fibrous and thick pseudocapsule that is almost undetectable in tumors from wild-type mice
(MGI Ref ID J:65383)
ultrastructurally, fibrosarcoma tumor neovessels formed in mutant mice are larger and less mature than tumor vessels from wild-type mice
(MGI Ref ID J:65383)
decreased metastatic potential
following implantation of T241 fibrosarcoma cells, only a limited number of mutants develop metastatic lesions in the lung and brain; in contrast, almost all of wild-type mice display metastases to the same locations
(MGI Ref ID J:65383)
notably, only mutants that survive for longer periods (2 months) after the injection develop these lesions, indicating a delay in metastasis
(MGI Ref ID J:65383)
decreased tumor growth/size
3 weeks after implantation of T241 fibrosarcoma cells, primary tumors from mutant mice are significantly smaller than tumors from wild-type mice
(MGI Ref ID J:65383)
consistent with tumor growth suppression, tumor tissues from mutant mice exhibit lower proliferative and higher apoptotic indices relative to tumor tissues from wild-type mice
(MGI Ref ID J:65383)
cellular phenotype
impaired macrophage chemotaxis
in response to skeletal muscle degeneration, homozygotes display a 50% reduction in macrophage recruitment at the injury site 48 hours after glycerol-induced injury
(MGI Ref ID J:68083)
digestive/alimentary phenotype
abnormal perineum morphology
in males with rectal prolapse, the perineal region is swollen on both sides of the evaginated rectal mucosa
(MGI Ref ID J:73613)
abnormal rectum morphology
in males with rectal prolapse, the rectal mucosa is exteriorized and evaginated
(MGI Ref ID J:73613)
rectal prolapse
in mutant males, rectal prolapse is irreducible and completely exteriorized by 12 months
(MGI Ref ID J:73613)
starting at 6 months, male (but not female) homozygotes show a high incidence of rectal prolapse
(MGI Ref ID J:73613)
endocrine/exocrine gland phenotype
herniated seminal vesicle
males with rectal prolapse develop an irreducible hernia of the seminal vesicles through the pelvic outlet and through a hiatus found between the iliococcygeus (ISC), the bulbocavrnosus (BC), and the tail
(MGI Ref ID J:73613)
this hernia results in chronic stretching and thinning of the ISC, BC, and levator ani (LA) pelvic floor muscles
(MGI Ref ID J:73613)
immune system phenotype
abnormal acute phase protein level
at 9 days after glycerol-induced injury of skeletal muscles, homozygotes exhibit abundant fibrin deposits in degenerating muscle fibers
(MGI Ref ID J:68083)
abnormal cytokine level
in a model of collagen-induced arthritis, arthritic homozygotes exhibit a significant reduction in TNF levels in the synovium relative to wild-type
(MGI Ref ID J:75303)
in a model of collagen-induced arthritis, arthritic homozygotes exhibit a significant reduction in interleukin-1beta levels in the synovium relative to wild-type
(MGI Ref ID J:75303)
decreased T cell proliferation
despite a normal antibody response to type II collagen, T cells from arthritic homozygotes show a reduced proliferative response and produce less interferon-gamma on antigen stimulation in vitro
(MGI Ref ID J:75303)
decreased inflammatory response
in response to glycerol-induced muscle degeneration, homozygotes display significantly reduced numbers of macrophages and neutrophils at the site of injury relative to wild-type
(MGI Ref ID J:68083)
decreased susceptibility to induced arthritis
in a model of collagen-induced arthritis, homozygotes develop a significantly milder disease than wild-type mice, with little inflammation and joint destruction
(MGI Ref ID J:75303)
in this chronic systemic model, the affected limbs of mutants are rigid but not swollen; arthritis is largely confined to the ankle joint, with most joints in the feet appearing normal
(MGI Ref ID J:75303)
surprisingly, the joints of arthritic homozygotes display minimal fibrin(ogen) deposition relative to wild-type
(MGI Ref ID J:75303)
impaired macrophage chemotaxis
in response to skeletal muscle degeneration, homozygotes display a 50% reduction in macrophage recruitment at the injury site 48 hours after glycerol-induced injury
(MGI Ref ID J:68083)
muscle phenotype
impaired skeletal muscle regeneration
at 5 days after injury, skeletal muscles from mutant mice appear edematous; in contrast to wild-type, no uninucleated, small myofibers are yet formed
(MGI Ref ID J:68083)
at 7 days after injury, most injured skeletal muscles appear necrotic and show extensive fibrosis
(MGI Ref ID J:68083)
at 9 and 20 days, numerous degenerated myotubes and fibrosis are still visible in mutant muscles whereas no signs of previous damage are detectable in wild-type muscles
(MGI Ref ID J:68083)
in response to glycerol-induced injury, homozygotes exhibit a severe skeletal muscle regeneration defect relative to wild-type; this defect is apparent at 5 days but is most striking at 9 and 20 days after injury
(MGI Ref ID J:68083)
systemic fibrinogen depletion via ancrod administration restores muscle regeneration: 9 days after injury, ancrod-treated mutants exhibit improved muscle regeneration, with centrally located nuclei inside the regenerated fibers
(MGI Ref ID J:68083)
myopathy
males with rectal prolapse, exhibit myopathic damage in the affected pelvic floor muscles (ISC, BC and LA)
(MGI Ref ID J:73613)
most affected myofibers have centrally located nuclei; some show basophilic degeneration in the absence of denervation, fibrosis or inflammation
(MGI Ref ID J:73613)
reproductive system phenotype
abnormal perineum morphology
in males with rectal prolapse, the perineal region is swollen on both sides of the evaginated rectal mucosa
(MGI Ref ID J:73613)
herniated seminal vesicle
males with rectal prolapse develop an irreducible hernia of the seminal vesicles through the pelvic outlet and through a hiatus found between the iliococcygeus (ISC), the bulbocavrnosus (BC), and the tail
(MGI Ref ID J:73613)
this hernia results in chronic stretching and thinning of the ISC, BC, and levator ani (LA) pelvic floor muscles
(MGI Ref ID J:73613)
skeleton phenotype
decreased susceptibility to induced arthritis
in a model of collagen-induced arthritis, homozygotes develop a significantly milder disease than wild-type mice, with little inflammation and joint destruction
(MGI Ref ID J:75303)
in this chronic systemic model, the affected limbs of mutants are rigid but not swollen; arthritis is largely confined to the ankle joint, with most joints in the feet appearing normal
(MGI Ref ID J:75303)
surprisingly, the joints of arthritic homozygotes display minimal fibrin(ogen) deposition relative to wild-type
(MGI Ref ID J:75303)
homeostasis/metabolism phenotype
abnormal acute phase protein level
at 9 days after glycerol-induced injury of skeletal muscles, homozygotes exhibit abundant fibrin deposits in degenerating muscle fibers
(MGI Ref ID J:68083)
abnormal cytokine level
in a model of collagen-induced arthritis, arthritic homozygotes exhibit a significant reduction in TNF levels in the synovium relative to wild-type
(MGI Ref ID J:75303)
in a model of collagen-induced arthritis, arthritic homozygotes exhibit a significant reduction in interleukin-1beta levels in the synovium relative to wild-type
(MGI Ref ID J:75303)
hematopoietic system phenotype
decreased T cell proliferation
despite a normal antibody response to type II collagen, T cells from arthritic homozygotes show a reduced proliferative response and produce less interferon-gamma on antigen stimulation in vitro
(MGI Ref ID J:75303)
impaired macrophage chemotaxis
in response to skeletal muscle degeneration, homozygotes display a 50% reduction in macrophage recruitment at the injury site 48 hours after glycerol-induced injury
(MGI Ref ID J:68083)
Genotype: Plau^tm1Mlg/Plau^tm1Mlg
involves: 129S2/SvPas * C57BL/6
mortality/aging
mortality/aging
homozygotes display a normal lifespan relative to wild-type mice
(MGI Ref ID J:17427)
respiratory system phenotype
pulmonary interstitial fibrosis
14 days after bleomycin treatment, homozygotes exhibit an increase in lung hydroxyproline (collagen) content that is comparable to that observed in bleomycin-treated wild-type mice
(MGI Ref ID J:63134)
62% of bleomycin-treated homozygotes die as early as ~7 days after treatment, possibly as a result of extensive fibrosis
(MGI Ref ID J:63134)
histological analysis 14 days after lung injury indicates extensive interstitial fibrosis in mutant mice relative to wild-type; however, no hemorrhage or extensive collagen deposition is observed
(MGI Ref ID J:63134)
vision/eye phenotype
abnormal eyelid morphology
at ~26 weeks of age, 5% homozygotes display severe non-healing ulcerations at the eyelids
(MGI Ref ID J:17427)
decreased susceptibility to induced choroidal neovascularization
in response to laser-induced injury of the Bruch's membrane, homozygotes display almost complete absence of choroidal neovascularization (CNV) at the site of trauma; in contrast, wild-type mice show a robust neovascular reaction
(MGI Ref ID J:82604)
resistance to CNV is associated with excessive fibrinogen-fibrin deposition at the site of choroidal trauma and in retinal vessels
(MGI Ref ID J:82604)
nervous system phenotype
nervous system phenotype
Abeta40 and 42 levels are not increased in mutant brains relative to controls
(MGI Ref ID J:104962)
homozygotes subjected to focal cerebral ischemia induced by persistent occlusion of the left middle cerebral artery produce an infarct with a size that is comparable to that produced in wild-type mice
(MGI Ref ID J:55243)
homeostasis/metabolism phenotype
abnormal acute phase protein level
after laser-induced injury of the Bruch's membrane, homozygotes show massive accumulation of fibrinogen-fibrin both in the retinal vessels, and in the bottom of the laser-induced trauma
(MGI Ref ID J:82604)
bleomycin-treated homozygotes exhibit extensive areas of fibrin(ogen) deposition in the lung interstitium which are associated with areas of fibrosis
(MGI Ref ID J:63134)
abnormal circulating protein level
3-6 month-old mice have elevated levels of plasma amyloid beta 42 (Abeta42) and Abeta40; by 11 months of age, difference in levels between mutants and controls has increased significantly
(MGI Ref ID J:104962)
abnormal thrombosis
homozygotes occasionally exhibit small, focal fibrin deposits in the intestines and in the sinusoids of the liver and extensive fibrin deposits in the ulcerated skin, ear or prolapsed rectum
(MGI Ref ID J:17427)
in response to injection of pro-inflammatory endotoxin in the footpad, homozygotes exhibit overt venous thrombosis at a significantly higher incidence (90% versus 54%) and to a much larger extent than wild-type mice (60% of mutants show >4 thrombosed veins per tissue section versus only 15% in wild-type)s per tissue section versus only 15% in wild-type)
(MGI Ref ID J:17427)
craniofacial phenotype
abnormal outer ear morphology
at ~26 weeks of age, 5% of homozygotes display severe non-healing ulcerations at the ears around the ear tag and the face
(MGI Ref ID J:17427)
cellular phenotype
impaired macrophage chemotaxis
5 days after bleomycin treatment, homozygotes display a peak in lung macrophage levels that coincides with the peak time observed in wild-type mice; however, their marcophage levels are significantly reduced relative to wild-type
(MGI Ref ID J:63134)
7 days after bleomycin treatment, mutant and wild-type mice show a similar decrease in the number and percentage of macrophages found in the lung
(MGI Ref ID J:63134)
growth/size/body region phenotype
abnormal outer ear morphology
at ~26 weeks of age, 5% of homozygotes display severe non-healing ulcerations at the ears around the ear tag and the face
(MGI Ref ID J:17427)
growth/size/body region phenotype
at 5 weeks of age, homozygotes exhibit a normal body weight relative to wild-type mice
(MGI Ref ID J:17427)
cardiovascular system phenotype
cardiac interstitial fibrosis
in response to pressure overload, homozygotes show only minimal signs of maladaptation (i.e. myolysis, fibrosis or increased intercapillary distance) relative to wild-type mice
(MGI Ref ID J:95236)
decreased susceptibility to induced choroidal neovascularization
in response to laser-induced injury of the Bruch's membrane, homozygotes display almost complete absence of choroidal neovascularization (CNV) at the site of trauma; in contrast, wild-type mice show a robust neovascular reaction
(MGI Ref ID J:82604)
resistance to CNV is associated with excessive fibrinogen-fibrin deposition at the site of choroidal trauma and in retinal vessels
(MGI Ref ID J:82604)
heart left ventricle hypertrophy
after transverse aortic banding (TAB), i.e. acute pressure overload, homozygotes remain significantly protected against LV hypertrophy for at least 7 weeks
(MGI Ref ID J:95236)
at 7 weeks after TAB, LV systolic dysfunction and dilatation are only marginally detectable without signs of pulmonary edema
(MGI Ref ID J:95236)
homozygotes display only a 20% increase in LV/body ratio and only a 22% increase in LV cardiomyocyte size relative to wild-type (~35% and ~40%, respectively)
(MGI Ref ID J:95236)
increased ventricle muscle contractility
at 7 weeks after TAB, homozygotes exhibit increased LV contractility, indicating normal fractional shortening with no cardiac failure or pulmonary congestion
(MGI Ref ID J:95236)
digestive/alimentary phenotype
rectal prolapse
at ~22 weeks of age, 9% of homozygotes display rectal prolapse of a non-infectious origin
(MGI Ref ID J:17427)
hearing/vestibular/ear phenotype
abnormal outer ear morphology
at ~26 weeks of age, 5% of homozygotes display severe non-healing ulcerations at the ears around the ear tag and the face
(MGI Ref ID J:17427)
hematopoietic system phenotype
abnormal macrophage physiology
in contrast to wild-type, homozygotes exhibit no plasminogen-dependent breakdown of 125I-fibrin-labeled matrix and of 3H-proline-labeled subendothelial breakdown by thioglycollate-activated macrohages; invasion of macrophages into the peritoneal cavity remains unaffectedmains unaffected
(MGI Ref ID J:17427)
abnormal neutrophil physiology
48 hours after intranasal inoculation with S. pneumoniae, homozygotes exhibit an enhanced antibacterial host defense, with less pneumococci in their lungs and increased neutrophil influx in the bronchoalveolar lavage fluid but no reduction in mortality relative to wild-typelative to wild-type
(MGI Ref ID J:75573)
in contrast, mutant neutrophils show normal agonist-stimulated release of specific granules relative to wild-type neutrophils
(MGI Ref ID J:91980)
in response to fMLP, mutant neutrophils exhibit reduced neutrophil exocytosis of azurophilic granules (as shown by reduced myeloperoxidase release); however, this defect is not corrected by repletion with extracellular uPA
(MGI Ref ID J:91980)
relative to wild-type, purified neutrophils from mutant mice exhibit a ~50% reduction in superoxide production in response to fMLP (a potent chemotaxin and activator of neutrophils) across the entire dose range tested; repletion with murine uPA completely reverses the defect in superoxide generation reverses the defect in superoxide generation
(MGI Ref ID J:91980)
hematopoietic system phenotype
homozygotes exhibit normal spontaneous lysis of a 125I-fibrin-labeled pulmonary plasma clot relative to wild-type
(MGI Ref ID J:17427)
impaired granulocyte bactericidal activity
in vitro, purified neutrophils from mutant mice display significant defects in several aspects of the antibacterial neutrophil activation process that lead to E. coli killing and effective host defense
(MGI Ref ID J:91980)
impaired macrophage chemotaxis
5 days after bleomycin treatment, homozygotes display a peak in lung macrophage levels that coincides with the peak time observed in wild-type mice; however, their marcophage levels are significantly reduced relative to wild-type
(MGI Ref ID J:63134)
7 days after bleomycin treatment, mutant and wild-type mice show a similar decrease in the number and percentage of macrophages found in the lung
(MGI Ref ID J:63134)
impaired neutrophil phagocytosis
in vitro, purified neutrophils from mutant mice exhibit a significant reduction in phagocytosis of E. coli at all time points; repletion with murine uPA substantially reverses the defect in neutrophil phagocytosis
(MGI Ref ID J:91980)
increased lymphocyte cell number
at day 7 post-treatment, the decline in macrophage counts coincides with an increase in the percentage of lymphocytes found in the lungs of bleomycin-treated mice
(MGI Ref ID J:63134)
immune system phenotype
abnormal acute phase protein level
after laser-induced injury of the Bruch's membrane, homozygotes show massive accumulation of fibrinogen-fibrin both in the retinal vessels, and in the bottom of the laser-induced trauma
(MGI Ref ID J:82604)
bleomycin-treated homozygotes exhibit extensive areas of fibrin(ogen) deposition in the lung interstitium which are associated with areas of fibrosis
(MGI Ref ID J:63134)
abnormal cell-mediated immunity
homozygotes fail to generate a type 1 immune response in the lung during pulmonary fungal infection with C. neoformans
(MGI Ref ID J:95638)
homozygotes fail to generate a type 2 immune response following schistosomal antigen challenge
(MGI Ref ID J:87817)
in response to C. neoformans infection, homozygotes show impaired T cell proliferation in regional lymph nodes and fail to produce high levels of T1 cytokines (IFN-gamma and IL-12) in the lung; instead, mutants exhibit increased levels of IL-5, a T2 cytokineine
(MGI Ref ID J:95638)
in response to schistosomal egg antigen (SEA), homozygotes fail to develop a delayed-type hypersensitivity response to SEA, do not polarize Ig production to IgE, fail to produce high levels of IL-4, IL-5, or IL-13 and generate pulmonary granulomas that are deficient in eosinophilse deficient in eosinophils
(MGI Ref ID J:87817)
abnormal macrophage physiology
in contrast to wild-type, homozygotes exhibit no plasminogen-dependent breakdown of 125I-fibrin-labeled matrix and of 3H-proline-labeled subendothelial breakdown by thioglycollate-activated macrohages; invasion of macrophages into the peritoneal cavity remains unaffectedmains unaffected
(MGI Ref ID J:17427)
abnormal neutrophil physiology
48 hours after intranasal inoculation with S. pneumoniae, homozygotes exhibit an enhanced antibacterial host defense, with less pneumococci in their lungs and increased neutrophil influx in the bronchoalveolar lavage fluid but no reduction in mortality relative to wild-typelative to wild-type
(MGI Ref ID J:75573)
in contrast, mutant neutrophils show normal agonist-stimulated release of specific granules relative to wild-type neutrophils
(MGI Ref ID J:91980)
in response to fMLP, mutant neutrophils exhibit reduced neutrophil exocytosis of azurophilic granules (as shown by reduced myeloperoxidase release); however, this defect is not corrected by repletion with extracellular uPA
(MGI Ref ID J:91980)
relative to wild-type, purified neutrophils from mutant mice exhibit a ~50% reduction in superoxide production in response to fMLP (a potent chemotaxin and activator of neutrophils) across the entire dose range tested; repletion with murine uPA completely reverses the defect in superoxide generation reverses the defect in superoxide generation
(MGI Ref ID J:91980)
impaired granulocyte bactericidal activity
in vitro, purified neutrophils from mutant mice display significant defects in several aspects of the antibacterial neutrophil activation process that lead to E. coli killing and effective host defense
(MGI Ref ID J:91980)
impaired macrophage chemotaxis
5 days after bleomycin treatment, homozygotes display a peak in lung macrophage levels that coincides with the peak time observed in wild-type mice; however, their marcophage levels are significantly reduced relative to wild-type
(MGI Ref ID J:63134)
7 days after bleomycin treatment, mutant and wild-type mice show a similar decrease in the number and percentage of macrophages found in the lung
(MGI Ref ID J:63134)
impaired neutrophil phagocytosis
in vitro, purified neutrophils from mutant mice exhibit a significant reduction in phagocytosis of E. coli at all time points; repletion with murine uPA substantially reverses the defect in neutrophil phagocytosis
(MGI Ref ID J:91980)
increased lymphocyte cell number
at day 7 post-treatment, the decline in macrophage counts coincides with an increase in the percentage of lymphocytes found in the lungs of bleomycin-treated mice
(MGI Ref ID J:63134)
increased susceptibility to fungal infection
21 days after inoculation with Cryptococcus neoformans, homozygotes contain significantly higher lung CFUs than wild-type mice
(MGI Ref ID J:95637)
C. neoformans-infected mutants disseminate the fungal pathogen to their spleen; eventually 15 out of 19 mutants (versus 3/19 wild-type) die from fungal meningitis
(MGI Ref ID J:95637)
increased susceptibility to parasitic infection
when primed homozygotes are challenged with schistosomal egg antigen (SEA) they exhibit a severe immune defect in response to this T2-eliciting antigen
(MGI Ref ID J:87817)
muscle phenotype
increased ventricle muscle contractility
at 7 weeks after TAB, homozygotes exhibit increased LV contractility, indicating normal fractional shortening with no cardiac failure or pulmonary congestion
(MGI Ref ID J:95236)
reproductive system phenotype
reproductive system phenotype
homozygotes display normal litter size and frequency of litters relative to wild-type mice
(MGI Ref ID J:17427)

References

Carmeliet P; Schoonjans L; Kieckens L; Ream B; Degen J; Bronson R; De Vos R; van den Oord JJ; Collen D; Mulligan RC. 1994. Physiological consequences of loss of plasminogen activator gene function in mice. Nature 368(6470):419-24. PubMed: 8133887 MGI: J:17427

Additional References
Dewerchin M; Nuffelen AV; Wallays G; Bouche A; Moons L; Carmeliet P; Mulligan RC; Collen D. 1996. Generation and characterization of urokinase receptor-deficient mice. J Clin Invest 97(3):870-8. PubMed: 8609247 MGI: J:31253

Additional - Plau^tm1Mlg related
Abraham E; Gyetko MR; Kuhn K; Arcaroli J; Strassheim D; Park JS; Shetty S; Idell S. 2003. Urokinase-type plasminogen activator potentiates lipopolysaccharide-induced neutrophil activation. J Immunol 170(11):5644-51. PubMed: 12759445 MGI: J:131136
Almholt K; Lund LR; Rygaard J; Nielsen BS; Dano K; Romer J; Johnsen M. 2005. Reduced metastasis of transgenic mammary cancer in urokinase-deficient mice. Int J Cancer 113(4):525-32. PubMed: 15472905 MGI: J:94645
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Uchida HA; Poduri A; Subramanian V; Cassis LA; Daugherty A. 2011. Urokinase-type plasminogen activator deficiency in bone marrow-derived cells augments rupture of angiotensin II-induced abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 31(12):2845-52. PubMed: 21868698 MGI: J:191466
Uhrin P; Schofer C; Zaujec J; Ryban L; Hilpert M; Weipoltshammer K; Jerabek I; Pirtzkall I; Furtmuller M; Dewerchin M; Binder BR; Geiger M. 2007. Male fertility and protein C inhibitor/plasminogen activator inhibitor-3 (PCI): localization of PCI in mouse testis and failure of single plasminogen activator knockout to restore spermatogenesis in PCI-deficient mice. Fertil Steril 88(4 Suppl):1049-57. PubMed: 17434507 MGI: J:129635
Van Den Broeck T; Stevenaert F; Taveirne S; Debacker V; Vangestel C; Vandekerckhove B; Taghon T; Matthys P; Plum J; Held W; Dewerchin M; Yokoyama WM; Leclercq G. 2008. Ly49E-dependent inhibition of natural killer cells by urokinase plasminogen activator. Blood 112(13):5046-51. PubMed: 18784372 MGI: J:143621
Wei C; Moller CC; Altintas MM; Li J; Schwarz K; Zacchigna S; Xie L; Henger A; Schmid H; Rastaldi MP; Cowan P; Kretzler M; Parrilla R; Bendayan M; Gupta V; Nikolic B; Kalluri R; Carmeliet P; Mundel P; Reiser J. 2008. Modification of kidney barrier function by the urokinase receptor. Nat Med 14(1):55-63. PubMed: 18084301 MGI: J:130835
Weiler-Guettler H; Christie PD; Beeler DL; Healy AM; Hancock WW; Rayburn H; Edelberg JM; Rosenberg RD. 1998. A targeted point mutation in thrombomodulin generates viable mice with a prethrombotic state. J Clin Invest 101(9):1983-91. PubMed: 9576763 MGI: J:47676
Wu F; Catano M; Echeverry R; Torre E; Haile WB; An J; Chen C; Cheng L; Nicholson A; Tong FC; Park J; Yepes M. 2014. Urokinase-type plasminogen activator promotes dendritic spine recovery and improves neurological outcome following ischemic stroke. J Neurosci 34(43):14219-32. PubMed: 25339736 MGI: J:217155
Yamaguchi I; Lopez-Guisa JM; Cai X; Collins SJ; Okamura DM; Eddy AA. 2007. Endogenous urokinase lacks antifibrotic activity during progressive renal injury. Am J Physiol Renal Physiol 293(1):F12-9. PubMed: 17356128 MGI: J:141660
Yang YH; Carmeliet P; Hamilton JA. 2001. Tissue-type plasminogen activator deficiency exacerbates arthritis. J Immunol 167(2):1047-52. PubMed: 11441114 MGI: J:120523
Yepes M; Sandkvist M; Moore EG; Bugge TH; Strickland DK; Lawrence DA. 2003. Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein. J Clin Invest 112(10):1533-40. PubMed: 14617754 MGI: J:119309
Yiou R; Delmas V; Carmeliet P; Gherardi RK; Barlovatz-Meimon G; Chopin DK; Abbou CC; Lefaucheur JP. 2001. The pathophysiology of pelvic floor disorders: evidence from a histomorphologic study of the perineum and a mouse model of rectal prolapse. J Anat 199(Pt 5):599-607. PubMed: 11760891 MGI: J:73613
de Giorgio-Miller A; Bottoms S; Laurent G; Carmeliet P; Herrick S. 2005. Fibrin-induced skin fibrosis in mice deficient in tissue plasminogen activator. Am J Pathol 167(3):721-32. PubMed: 16127152 MGI: J:100676

Allele Name	targeted mutation 1, Richard C Mulligan
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	UPA-; u-PA^-; uPA-
Gene Symbol and Name	Plau, plasminogen activator, urokinase
Gene Synonym(s)	ATF; BDPLT5; QPD; UPA; UPAM; URK; u-PA; uPA; urokinase-type plasminogen activator
Strain of Origin	129S2/SvPas
Chromosome	14
Molecular Note	The gene was disrupted using neomycin resistance cassette. The vector replaced genomic sequences encompassing all but 23 amino acids of the coding sequence. Targeting was confirmed by the absence of gene specific mRNA and immunoreactivity.
Mutations Made By	Dr. Peter Carmeliet, University of Leuven

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Plautm1Mlg

Allele Symbol: Plautm1Mlg

Disease Terms

Research Areas By Genotype

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

Genotype: Plautm1Mlg related

Mammalian Phenotype Terms by Genotype

Genotype: Plautm1Mlg/Plautm1MlgB6.129S2-Plautm1Mlg

mortality/aging

immune system phenotype

liver/biliary system phenotype

homeostasis/metabolism phenotype

respiratory system phenotype

adipose tissue phenotype

growth/size/body region phenotype

Genotype: Plautm1Mlg/Plautm1Mlgeither: B6.Cg-Plautm1Mlg or (involves: Black Swiss * C57BL/6)

homeostasis/metabolism phenotype

Genotype: Plautm1Mlg/Plautm1MlgB6.Cg-Plautm1Mlg

neoplasm

cellular phenotype

digestive/alimentary phenotype

endocrine/exocrine gland phenotype

immune system phenotype

muscle phenotype

reproductive system phenotype

skeleton phenotype

homeostasis/metabolism phenotype

hematopoietic system phenotype

Genotype: Plautm1Mlg/Plautm1Mlginvolves: 129S2/SvPas * C57BL/6

mortality/aging

respiratory system phenotype

vision/eye phenotype

nervous system phenotype

homeostasis/metabolism phenotype

craniofacial phenotype

cellular phenotype

growth/size/body region phenotype

cardiovascular system phenotype

digestive/alimentary phenotype

hearing/vestibular/ear phenotype

hematopoietic system phenotype

immune system phenotype

muscle phenotype

reproductive system phenotype

References

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Additional - Plautm1Mlg related

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

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Plau^tm1Mlg

Allele Symbol: Plau^tm1Mlg

Genotype: Plau^tm1Mlg related

Genotype: Plau^tm1Mlg/Plau^tm1Mlg
B6.129S2-Plau^tm1Mlg

Genotype: Plau^tm1Mlg/Plau^tm1Mlg
either: B6.Cg-Plau^tm1Mlg or (involves: Black Swiss * C57BL/6)

Genotype: Plau^tm1Mlg/Plau^tm1Mlg
B6.Cg-Plau^tm1Mlg

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

Additional - Plau^tm1Mlg related