Overview

These integrin beta 3 targeted mutant mice exhibit significant embryonic lethality attributed to fetal hemorrhaging and placental defects. This mutant mouse strain represents a model that may be useful in studies related to Glanzmann thrombasthenia.

Donating Investigator

Dr. Richard Hynes, Massachusetts Institute of Technology

Genetic overview

Genetic Background	Generation

Itgb3^tm1Hyn

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Itgb3	integrin beta 3

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Research Applications

Cardiovascular Research
Hematological Research
Developmental Biology Research
Internal/Organ Research

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Details

Detailed Description

Mice that are homozygous for this targeted allele are viable and fertile. No gene product (protein) is detected on the surface of platelets. Significant (50%) embryonic lethality attributed to fetal hemorrhaging and placental defects is observed. Until three weeks of age, additional pup loss may occur due to hemorrhaging in the skin and gastrointestinal tract. Gastrointestinal tract bleeding is commonly observed in adults and is frequently associated with an enlarged spleen. Erythrocyte number, hemoglobin, hematocrits and thrombus formation are all reduced while bleeding time is prolonged. Varying degrees of liver and kidney necrosis are also observed. Although increased numbers of osteoclasts are observed (3.5 fold over that seen in heterozygotes) they appear to be dysfunctional, having a reduced ability to resorb whale dentin in vitro. Mice are osteosclerotic and hypocalcemic. Enhanced tumor angiogenesis and vascular endothelial growth factor-induced blood vessel growth are observed. This mutant mouse strain represents a model that may be useful in studies related to Glanzmann thrombasthenia.

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

A targeting vector containing a neomycin resistance gene driven by the mouse phosphoglycerate kinase promoter was used to disrupt exons 1 and 2 of the targeted gene. The construct was transfected into 129S2/SvPas-derived D3 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting chimeric animals were backcrossed to 129S4/AvJae for more than 7 generations by the donating laboratory.

Selected References

Hodivala-Dilke KM; McHugh KP; Tsakiris DA; Rayburn H; Crowley D; Ullman-Cullere M; Ross FP; Coller BS; Teitelbaum S; Hynes RO. 1999. Beta3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival. J Clin Invest 103(2):229-38PubMed: 9916135 MGI: J:52262

View All References

Genetics

Itgb3^tm1Hyn

Allele Symbol: Itgb3^tm1Hyn

Allele Name	targeted mutation 1, Richard Hynes
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	Beta3; beta3 KO; beta3^-
Gene Symbol and Name	Itgb3, integrin beta 3
Gene Synonym(s)
Strain of Origin	129S2/SvPas
Chromosome	11
Molecular Note	A PGK-neomycin resistance cassette replaced 1.4 kb of sequence including exons I and II. FACS, immunoprecipitation, and immunofluorescence analyses did not detect protein expression in platelets and MEFs from homozygous mutant animals.
Mutations Made By	Dr. Richard Hynes, Massachusetts Institute of Technology

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

platelet-type bleeding disorder 16

Research Areas By Phenotype

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

Genotype: Itgb3^tm1Hyn related

Cardiovascular Research
- Vascular Defects
Hematological Research
- Clotting Defects
- Platelet Defects

Developmental Biology Research
- Embryonic Lethality (Homozygous)
  - incomplete
Internal/Organ Research
- Skeleton
  - Bone

Mammalian Phenotype Terms by Genotype

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

Genotype: Itgb3^tm1Hyn/Itgb3⁺
involves: 129S2/SvPas * C57BL/6

homeostasis/metabolism phenotype

increased response of heart to induced stress
- heart rate is significantly decreased 7 days after pressure overload by transverse aortic constriction surgery (TAC) compared to wild-type
- impairment of systolic and diastolic function after transverse aortic constriction is more severe than in wild-type controls

muscle phenotype

heart left ventricle hypertrophy
- spontaneous

cardiovascular system phenotype

increased response of heart to induced stress
- impairment of systolic and diastolic function after transverse aortic constriction is more severe than in wild-type controls
- heart rate is significantly decreased 7 days after pressure overload by transverse aortic constriction surgery (TAC) compared to wild-type

increased left ventricle weight
- left ventricle weight to body weight ratio is increased

heart left ventricle hypertrophy
- spontaneous

cardiac hypertrophy
- the hypertrophy phenotype is intermediate between homozygous null and wild-type mice

increased heart weight
- heart weight to body weight ratio is increased

decreased heart rate
- heart rate is significantly decreased 7 days after pressure overload by transverse aortic constriction surgery (TAC) compared to wild-type

growth/size/body region phenotype

cardiac hypertrophy
- the hypertrophy phenotype is intermediate between homozygous null and wild-type mice

increased heart weight
- heart weight to body weight ratio is increased

increased left ventricle weight
- left ventricle weight to body weight ratio is increased

heart left ventricle hypertrophy
- spontaneous

Genotype: Itgb3^tm1Hyn/Itgb3^tm1Hyn
involves: 129S2/SvPas * BALB/c

cellular phenotype

maternal effect
- gotes
- pups and fetuses from homozygous females immunized two or four times with wild-type platelets, respectively, and mated with wild-type males exhibit hemorrhaging, reduced platelets and increased mortality, a phenotype similar to human fetal and neonatal alloimmune thrombocytopenia
- heterozygous pups from non-immunized females mated with wild-type males exhibit normal platelets counts, indicating that maternal antibodies of the pregnant females and not pup genotype is responsible for the reduced platelets and hemorrhaging in heterozygotes
- loimmune thrombocytopenia

mortality/aging

pregnancy-related premature death
- one of three homozygous females immunized four times with wild-type platelets and mated with a wild-type male, died during delivery after a 3-week pregnancy

reproductive system phenotype

abnormal miscarriage rate
- homozygous females immunized with wild-type platelets and mated with wild-type males, exhibit miscarriages due to internal organ bleeding of fetuses; females immunized 4 times show more miscarriages than females immunized 2 times with wild-type platelets

hematopoietic system phenotype

increased IgG level
- however, homozygous preimmunized females do not show any detectable anti-Itgb3 IgG after the first and second deliveries after mating with wild-type males; low levels of anti-Itgb3 antibodies are seen in the third and subsequent deliveries
- titer of maternal IgG against Itgb3 in homozygous females increases with the number of times females are immunized with wild-type platelets

immune system phenotype

increased IgG level
- however, homozygous preimmunized females do not show any detectable anti-Itgb3 IgG after the first and second deliveries after mating with wild-type males; low levels of anti-Itgb3 antibodies are seen in the third and subsequent deliveries
- titer of maternal IgG against Itgb3 in homozygous females increases with the number of times females are immunized with wild-type platelets

mammalian phenotype

immune system phenotype
- Normal - both T-helper 1 and T-helper 2 immune responses to platelet Itgb3 antigen exist in mutants

Genotype: Itgb3^tm1Hyn/Itgb3^tm1Hyn
involves: 129S2/SvPas * C57BL/6

cardiovascular system phenotype

increased angiogenesis
- blood-vessel infiltration of matrigel implants impregnated with VEGF is significantly elevated
- however, no increase in vessel density is seen on scruff skin
- in the presence of VEGF, the total number of vessel sprouts in aortic rings embedded in Matrigel is significantly higher compared to wild-type

cardiac hypertrophy
- in 12-week-old spontaneous cardiac hypertrophy occurs in the absence of provocative stimulation

increased left ventricle diastolic pressure
- left ventricular end-diastolic pressure is significantly increased 7 days after pressure overload by transverse aortic constriction surgery (TAC) compared to wild-type
- minimal change in pressure per unit time is significantly increased 7 days after pressure overload by TAC surgery compared to wild-type
- the maximal change in pressure per unit time is significantly decreased 7 days after pressure overload by TAC surgery compared to wild-type

increased response of heart to induced stress
- impairment of systolic and diastolic function after transverse aortic constriction is more severe than in wild-type controls
- cardiac tissue exhibits marked round cell infiltration 7 days after transverse aortic constriction surgery

increased left ventricle weight
- left ventricle weight to body weight ratio is increased by 4 weeks of age

increased heart weight
- heart weight to body weight ratio is increased

uterine hemorrhage

gastrointestinal hemorrhage
- in some homozygous newborn pups which die before weaning and in many of the surviving homozygous adult mice

heart left ventricle hypertrophy

decreased cardiac muscle contractility
- a significantly impaired contractile response to infusion of the inotropic agent Dobutamine

decreased left ventricle systolic pressure
- 12-week-old mice have reduced systolic function compared to wild-type littermates
- left ventricular peak systolic pressure is significantly decreased 7 days after pressure overload by transverse aortic constriction surgery (TAC) compared to wild-type
- left ventricular peak systolic pressure is decreased in 12-week-old mice

abnormal induced retinal neovascularization
- hypoxia-induced retinal neovascularization is significantly elevated as measure by numbers of vascular glomeruli at P17

decreased heart rate
- heart rate is significantly decreased 7 days after pressure overload by transverse aortic constriction surgery (TAC) compared to wild-type

hemorrhage
- some homozygous embryos and newborn pups displayed hemorrhage in the skin, in petechiae and in purpura, and appeared anemic

abnormal cardiac muscle relaxation
- diastolic relaxation is impaired (dP/dt min and tau (Glantz) are significantly increased)

abnormal tumor vascularization
- significantly elevated numbers of vessels per square millimeter of tumors, from injected cells, when compared with wild-type controls

skin hemorrhage

cellular phenotype

impaired macrophage chemotaxis
- peritoneal macrophages migrate less efficiently

renal necrosis
- enlarged glomeruli and dilated and necrotic proximal tubules containing proteinaceous deposits are found secondary to the excessive bleeding

abnormal cell adhesion
- endothelial cells showed background levels of adhesion and no migration on vitronectin

abnormal cell migration
- endothelial cells showed background levels of adhesion and no migration on vitronectin

hepatic necrosis
- centrilobular necrosis of the liver are found secondary to the excessive bleeding

digestive/alimentary phenotype

gastrointestinal hemorrhage
- in some homozygous newborn pups which die before weaning and in many of the surviving homozygous adult mice

embryo phenotype

abnormal trophoblast giant cell morphology
- within affected placentae of homozygous pregnant females, trophoblastic cells sometimes invaded the labyrinthine part of the placenta

abnormal placenta labyrinth morphology
- thickened cell layers in the labyrinth layer in approximately 25% of placentae of homozygous pregnant females which were associated with dead embryos
- within affected placentae, the space between endothelial layers was reduced with evidence of increased necrosis

pale placenta

growth/size/body region phenotype

enlarged spleen
- commonly associated with gastrointestinal bleeding

increased left ventricle weight
- left ventricle weight to body weight ratio is increased by 4 weeks of age

cardiac hypertrophy
- in 12-week-old spontaneous cardiac hypertrophy occurs in the absence of provocative stimulation

heart left ventricle hypertrophy

increased heart weight
- heart weight to body weight ratio is increased

hematopoietic system phenotype

extramedullary hematopoiesis
- found in animals with splenomegaly

abnormal platelet activation
- platelet isolated from homozygous mice shows reduced clot retraction and greatly reduced fibrinogen uptake in vitro
- platelet isolated from homozygous mice did not aggregate after ADP-induced activation in vitro
- reduced formation of thrombi in Shwartzman-like reaction, an experimental model of hemorrhagic vasculitis induced by subcutaneous injection of LPS followed 24 h later by an injection of TNF-alpha in the same place

decreased erythrocyte cell number
- in 8-12-week-old mice

reticulocytosis
- in 8-12-week-old mice

decreased hemoglobin content
- in 8-12-week-old mice

abnormal macrophage physiology
- peritoneal macrophages express significantly more Tnf and Il1b

anemia
- secondary to the excessive bleeding

increased monocyte cell number
- the monocyte count is dramatically increased in peripheral blood

decreased hematocrit
- in 8-12-week-old mice

enlarged spleen
- commonly associated with gastrointestinal bleeding

impaired macrophage chemotaxis
- peritoneal macrophages migrate less efficiently

homeostasis/metabolism phenotype

abnormal platelet activation
- platelet isolated from homozygous mice did not aggregate after ADP-induced activation in vitro
- reduced formation of thrombi in Shwartzman-like reaction, an experimental model of hemorrhagic vasculitis induced by subcutaneous injection of LPS followed 24 h later by an injection of TNF-alpha in the same place
- platelet isolated from homozygous mice shows reduced clot retraction and greatly reduced fibrinogen uptake in vitro

increased bleeding time
- impaired hemostasis as evidenced by failure to arrest bleeding within 10 minutes following tail resection

increased response of heart to induced stress
- cardiac tissue exhibits marked round cell infiltration 7 days after transverse aortic constriction surgery
- impairment of systolic and diastolic function after transverse aortic constriction is more severe than in wild-type controls

immune system phenotype

enlarged spleen
- commonly associated with gastrointestinal bleeding

impaired macrophage chemotaxis
- peritoneal macrophages migrate less efficiently

abnormal macrophage physiology
- peritoneal macrophages express significantly more Tnf and Il1b

dermatitis
- ulcerative dermatitis in some homozygous animals undergoing crisis

myositis
- cardiac tissue exhibits marked round cell infiltration 7 days after transverse aortic constriction surgery

increased monocyte cell number
- the monocyte count is dramatically increased in peripheral blood

integument phenotype

dermatitis
- ulcerative dermatitis in some homozygous animals undergoing crisis

petechiae
- petechiae are observed around the mouth, indicating bleeding under the epidermis

purpura
- purpura are observed on the forelimb, indicating bleeding within the dermis

skin hemorrhage

liver/biliary system phenotype

hepatic necrosis
- centrilobular necrosis of the liver are found secondary to the excessive bleeding

mammalian phenotype

vision/eye phenotype
- Normal - the patterns of neovascularization in P7 retinas isolated from wild-type or homozygous mutant mice showed no obvious differences

mortality/aging

postnatal lethality, incomplete penetrance
- significant loss of homozygous pups up to three weeks of age due to hemorrhage

premature death
- some homozygous animals suffered acute blood loss and crisis which lead to premature death

muscle phenotype

heart left ventricle hypertrophy

myositis
- cardiac tissue exhibits marked round cell infiltration 7 days after transverse aortic constriction surgery

decreased cardiac muscle contractility
- a significantly impaired contractile response to infusion of the inotropic agent Dobutamine

abnormal cardiac muscle relaxation
- diastolic relaxation is impaired (dP/dt min and tau (Glantz) are significantly increased)

neoplasm

increased tumor growth/size
- tumor size is enhanced significantly when injected with murine melanoma (B16F0) or lung carcinoma (CMT19T) cells

abnormal tumor vascularization
- significantly elevated numbers of vessels per square millimeter of tumors, from injected cells, when compared with wild-type controls

renal/urinary system phenotype

renal necrosis
- enlarged glomeruli and dilated and necrotic proximal tubules containing proteinaceous deposits are found secondary to the excessive bleeding

reproductive system phenotype

abnormal miscarriage rate
- 9.5% of the embryos carried by homozygous mothers were found dead in utero at E14 and E17

reduced female fertility
- litter sizes of homozygous female were reduced significantly compared to wild-type

uterine hemorrhage

abnormal uterine environment
- compromised survival of embryos in homozygous mother as a result of placental defects and intrauterine hemorrhage

vision/eye phenotype

abnormal induced retinal neovascularization
- hypoxia-induced retinal neovascularization is significantly elevated as measure by numbers of vascular glomeruli at P17

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

Genotype: Itgb3^tm1Hyn/Itgb3^tm1Hyn
involves: 129S2/SvPas

cardiovascular system phenotype

abnormal physiological neovascularization
- increase in vascularization in wounds after 7 days of healing

homeostasis/metabolism phenotype

decreased circulating calcium level

enhanced wound healing
- dermal fibroblast recruitment in wounded tissue is significantly elevated with enhanced fibronectin and vitronectin deposition in granulation tissue
- re-epithelialization is accelerated significantly

increased transforming growth factor beta level
- platelets release twofold more TGF

abnormal platelet physiology
- platelets release twofold more TGF

immune system phenotype

abnormal osteoclast morphology
- the ruffled membrane is thick with blunted projections
- actin rings fail to form and actin is diffusely distributed, in a punctate pattern

abnormal osteoclast physiology
- bone marrow macrophages differentiate into osteoclasts that fail to spread

increased osteoclast cell number
- about a 3 fold increase per mm trabecular bone surface

decreased macrophage cell number
- number of macrophage in wounds is significantly lower than in wild-type wounds

integument phenotype

decreased keratinocyte proliferation
- in the hyperproliferative epidermal region 3 days after wounding

cellular phenotype

decreased keratinocyte proliferation
- in the hyperproliferative epidermal region 3 days after wounding

skeleton phenotype

abnormal osteoclast morphology
- the ruffled membrane is thick with blunted projections
- actin rings fail to form and actin is diffusely distributed, in a punctate pattern

abnormal osteoclast physiology
- bone marrow macrophages differentiate into osteoclasts that fail to spread

increased osteoclast cell number
- about a 3 fold increase per mm trabecular bone surface

increased trabecular bone thickness
- decreased ability of bone marrow macrophage derived osteoclasts to excavate whale dentin and produce well defined resorption lacunae

increased compact bone thickness
- increased bone mass

osteosclerosis
- increased bone mass

hematopoietic system phenotype

abnormal osteoclast physiology
- bone marrow macrophages differentiate into osteoclasts that fail to spread

abnormal osteoclast morphology
- actin rings fail to form and actin is diffusely distributed, in a punctate pattern
- the ruffled membrane is thick with blunted projections

abnormal platelet physiology
- platelets release twofold more TGF

decreased macrophage cell number
- number of macrophage in wounds is significantly lower than in wild-type wounds

increased osteoclast cell number
- about a 3 fold increase per mm trabecular bone surface

References

Hodivala-Dilke KM; McHugh KP; Tsakiris DA; Rayburn H; Crowley D; Ullman-Cullere M; Ross FP; Coller BS; Teitelbaum S; Hynes RO. 1999. Beta3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival. J Clin Invest 103(2):229-38PubMed: 9916135 MGI: J:52262

Additional - Itgb3^tm1Hyn related

Technical Support

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Genotyping Protocols
- Genotyping resources and troubleshooting
Breeding Considerations

When maintained as a live colony, homozygotes or heterozygotes may be bred.
- Additional Breeding and Husbandry Support
Citation
When using the 129S-Itgb3^tm1Hyn/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #008700 in your Materials and Methods section.

Animal Health Reports

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

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	Heterozygous for Itgb3<tm1Hyn>

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The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

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Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Selected References

Itgb3tm1Hyn

Allele Symbol: Itgb3tm1Hyn

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Research Areas By Phenotype

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

Genotype: Itgb3tm1Hyn related

Mammalian Phenotype Terms by Genotype

Genotype: Itgb3tm1Hyn/Itgb3+involves: 129S2/SvPas * C57BL/6

homeostasis/metabolism phenotype

muscle phenotype

cardiovascular system phenotype

growth/size/body region phenotype

Genotype: Itgb3tm1Hyn/Itgb3tm1Hyninvolves: 129S2/SvPas * BALB/c

cellular phenotype

mortality/aging

reproductive system phenotype

hematopoietic system phenotype

immune system phenotype

mammalian phenotype

Genotype: Itgb3tm1Hyn/Itgb3tm1Hyninvolves: 129S2/SvPas * C57BL/6

cardiovascular system phenotype

cellular phenotype

digestive/alimentary phenotype

embryo phenotype

growth/size/body region phenotype

hematopoietic system phenotype

homeostasis/metabolism phenotype

immune system phenotype

integument phenotype

liver/biliary system phenotype

mammalian phenotype

mortality/aging

muscle phenotype

neoplasm

renal/urinary system phenotype

reproductive system phenotype

vision/eye phenotype

Genotype: Itgb3tm1Hyn/Itgb3tm1Hyninvolves: 129S2/SvPas

cardiovascular system phenotype

homeostasis/metabolism phenotype

immune system phenotype

integument phenotype

cellular phenotype

skeleton phenotype

hematopoietic system phenotype

References

Additional - Itgb3tm1Hyn related

Genotyping Protocols

Breeding Considerations

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

Additional Use Restrictions Apply

Licensing Information

Itgb3^tm1Hyn

Allele Symbol: Itgb3^tm1Hyn

Genotype: Itgb3^tm1Hyn related

Genotype: Itgb3^tm1Hyn/Itgb3⁺
involves: 129S2/SvPas * C57BL/6

Genotype: Itgb3^tm1Hyn/Itgb3^tm1Hyn
involves: 129S2/SvPas * BALB/c

Genotype: Itgb3^tm1Hyn/Itgb3^tm1Hyn
involves: 129S2/SvPas * C57BL/6

Genotype: Itgb3^tm1Hyn/Itgb3^tm1Hyn
involves: 129S2/SvPas

Additional - Itgb3^tm1Hyn related