JAX
Mouse Strain Datasheet - 002509
B6.129S2-Plautm1Mlg/J
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
Genetic overview
| Genetic Background | Generation |
|---|---|
|
C57BL/6 |
|
Plautm1Mlg
| Allele Type | Gene Symbol | Gene Name |
|---|---|---|
| Targeted (Null/Knockout) | Plau | plasminogen activator, urokinase |
Research Applications
- Hematological Research
- Metabolism Research
- Neurobiology Research
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
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: 8133887MGI: J:17427
Plautm1Mlg
Allele Symbol: Plautm1Mlg
| 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 Terms
Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested.
Research Areas By Genotype
This mouse can be used to support research in many areas including:
Genotype: Plautm1Mlg related
- Hematological Research
- Clotting Defects
- Metabolism Research
- Neurobiology Research
- Alzheimer's Disease
Mammalian Phenotype Terms by Genotype
Genotype: Plautm1Mlg/Plautm1Mlg
B6.129S2-Plautm1Mlg
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
- 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 Plautm1.1Bug or Plaurtm1Jld 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
- 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: Plautm1Mlg/Plautm1Mlg
either: B6.Cg-Plautm1Mlg 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: Plautm1Mlg/Plautm1Mlg
B6.Cg-Plautm1Mlg
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
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
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: Plautm1Mlg/Plautm1Mlg
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: 8133887MGI: 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: 8609247MGI: J:31253
Additional - Plautm1Mlg 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: 12759445MGI: 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: 15472905MGI: J:94645
- Bajou K; Herkenne S; Thijssen VL; D'Amico S; Nguyen NQ; Bouche A; Tabruyn S; Srahna M; Carabin JY; Nivelles O; Paques C; Cornelissen I; Lion M; Noel A; Gils A; Vinckier S; Declerck PJ; Griffioen AW; Dewerchin M; Martial JA; Carmeliet P; Struman I. 2014. PAI-1 mediates the antiangiogenic and profibrinolytic effects of 16K prolactin. Nat Med 20(7):741-7. PubMed: 24929950MGI: J:227609
- Bdeir K; Murciano JC; Tomaszewski J; Koniaris L; Martinez J; Cines DB; Muzykantov VR; Higazi AA. 2000. Urokinase mediates fibrinolysis in the pulmonary microvasculature Blood 96(5):1820-6. PubMed: 10961882MGI: J:64220
- Bergers G; Brekken R; McMahon G; Vu TH; Itoh T; Tamaki K; Tanzawa K; Thorpe P; Itohara S; Werb Z; Hanahan D. 2000. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis Nat Cell Biol 2(10):737-44. PubMed: 11025665MGI: J:65019
- Bezerra JA; Currier AR; Melin-Aldana H; Sabla G; Bugge TH; Kombrinck KW; Degen JL. 2001. Plasminogen activators direct reorganization of the liver lobule after acute injury. Am J Pathol 158(3):921-9. PubMed: 11238040MGI: J:114282
- Bhandary YP; Shetty SK; Marudamuthu AS; Ji HL; Neuenschwander PF; Boggaram V; Morris GF; Fu J; Idell S; Shetty S. 2013. Regulation of Lung Injury and Fibrosis by p53-Mediated Changes in Urokinase and Plasminogen Activator Inhibitor-1. Am J Pathol 183(1):131-43. PubMed: 23665346MGI: J:197439
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