Overview

The PDGFRα^(S)J conditional knockin allele has the endogenous PDGFRα sequences replaced with a floxed-STOP cassette upstream of the constitutively active PDGFRαJ mutant isoform (V561D mutation). Following Cre-mediated excision of the floxed-STOP cassette, expression of the constitutively active mutant PDGFRα leads to high basal kinase activity without the addition of ligand. These mutant mice may be useful in studying PDGFR signaling in connective tissue development and homeostasis, systemic fibrosis diseases and human systemic sclerosis. As the PDGFRαJ is the most common PDGFRα juxtamembrane domain mutation found in human gastrointestinal stromal tumors (GISTs), these mice may also be used to investigate tumor-suppression in attenuating fibrotic diseases.

Donating Investigator

Dr. Philippe Soriano, Mount Sinai School of Medicine

Genetic overview

Genetic Background	Generation

Pdgfra^tm13Sor

Allele Type	Gene Symbol	Gene Name
Targeted (Conditional ready (e.g. floxed), Constitutively active, Humanized sequence)	Pdgfra	platelet derived growth factor receptor, alpha polypeptide

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Research Applications

Cardiovascular Research
Internal/Organ Research
Developmental Biology Research
Research Tools
Cancer Research
Immunology, Inflammation and Autoimmunity Research
Cell Biology Research
Dermatology Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

The PDGFRα^(S)J conditional knockin allele has the endogenous PDGFRα sequences replaced with a loxP-flanked PGKneo (lox-stop-lox) cassette upstream of the constitutively active PDGFRαJ mutant isoform. This V561D mutation in the juxtamembrane domain disrupts inhibitory contacts between the juxtamembrane and kinase domains, which are important for full auto-inhibition, and results in constitutive PDGFRα activity. Prior to Cre recombinase exposure, no expression of the constitutively active αJ mutant isoform is observed, and the mutant allele functions as a knockout. Mice homozygous for the PDGFRα^(S)J allele die during embryonic development. Heterozygous PDGFRα^(S)J mice are viable and fertile with no reported abnormalities. Following Cre recombinase-mediated excision of the floxed-STOP cassette, high basal kinase activity without the addition of ligand is observed in the cre-expressing tissues.

Of note, pan-deletion of the floxed-STOP cassette during development can be achieved by breeding PDGFRα^(S)J conditional knockin mice with Meox2^Cre mice expressing Cre recombinase in the early embryo (Stock No. 003755). Alternatively, widespread deletion of the floxed-STOP cassette in adult mice can be achieved by breeding PDGFRα^(S)J conditional knockin mice with ROSA26^CreER mice ubiquitously expressing a tamoxifen-inducible Cre recombinase (Stock No. 004847). Following tamoxifen treatment in the double mutant embryos/animals, widespread expression of the constitutively active PDGFRαJ leads to connective tissue hyperplasia in embryos and widespread organ fibrosis in adult mice (resembling human autoimmune disease systemic sclerosis). Organs affected are intestine (w polyps), skin, heart, skeletal muscle, kidney glomeruli and renal insterstitium. Vascular smooth muscle is not affected. When comparing widespread Cre recombinase-activated phenotypes of PDGFRαJ to PDGFRαK (see Stock No. 018433), PDGFRαJ expression results in a more attenuated fibrotic disease than PDGFRαK.

Development

To create the PDGFRα^(S)J targeting vector, Dr. Philippe Soriano (Mount Sinai School of Medicine) isolated a full-length mouse platelet derived growth factor α (Pdgfra) cDNA sequence and introduced a valine to aspartic acid substitution at codon 561 (V561D) of the juxtamembrane domain by site-directed mutagenesis. This αJ mutation results in a constitutively active mutant PDGFRα and is the most common PDGFRα juxtamembrane mutation found in human gastrointestinal stromal tumors (GISTs). A loxP-flanked PGKneo cassette (lox-stop-lox) was placed between the splice acceptor and the initiating codon of the mutant cDNA sequence. This construct replaced the endogenous Pdgfra exons 2-4 via electroporation into 129S4/SvJaeSor-derived AK7 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts, and the resulting chimeric males were mated with females to generate the PDGFRα^(S)J knockin mouse line. Heterozygous mice were bred to B6;129 mice harboring other mutations/transgenes, and/or to C57BL/6J wildtype, and/or C57BL/6NTac wildtype mice for several generations prior to sending to The Jackson Laboratory Repository. The donating investigator reports selecting PDGFRα^(S)J mice with no other mutations present for breeding. Upon arrival, mutant mice were bred to C57BL/6J inbred mice (Stock No. 000664) for at least one generation to establish The Jackson Laboratory Repository colony.

Control Suggestions

Wild-type from the colony

Approximate Controls

Additional Information

Considerations for Choosing Controls

Selected References

Olson LE ; Soriano P. 2009. Increased PDGFRalpha activation disrupts connective tissue development and drives systemic fibrosis. Dev Cell 16(2):303-13PubMed: 19217431 MGI: J:146617

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Genetics

Pdgfra^tm13Sor

Allele Symbol: Pdgfra^tm13Sor

Allele Name	targeted mutation 13, Philippe Soriano
Allele Type	Targeted (Conditional ready (e.g. floxed), Constitutively active, Humanized sequence)
Allele Synonym(s)	PDGFRalpha^(S)J
Gene Symbol and Name	Pdgfra, platelet derived growth factor receptor, alpha polypeptide
Gene Synonym(s)
Strain of Origin	129S4/SvJaeSor
Chromosome	5
Molecular Note	Exons 2 through 4 were replaced with a cDNA of the gene with nucleotide substitutions that result in an amino acid substitution of aspartic acid for valine at position 561 (V561D) preceded by a floxed neo-STOP cassette. This mutation is found in human patients with gastrointestinal stromal tumors and leads to a constitutively active form by disrupting the inhibitory conotacts between the juxtamembrane and kinase domain. Removal of the floxed neo-STOP cassette is necessary to achieve expression.
Mutations Made By	Dr. Philippe Soriano, Mount Sinai School of Medicine

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

Cardiovascular Research
- Other
- Heart Abnormalities
Internal/Organ Research
- Kidney Defects
  - Renal tubulointerstitial lesions
- Heart Abnormalities
- Gastrointestinal Defects
Developmental Biology Research
- Internal/Organ Defects
  - kidney
  - heart
  - skin
- Embryonic Lethality (Homozygous)
- Mesodermal Defects
  - Myogenesis Defects
Research Tools
- Cancer Research
  - tumor immunology
  - anti-tumor activity
- Immunology, Inflammation and Autoimmunity Research
- Genetics Research
  - Mutagenesis and Transgenesis: Cre-lox System
  - Tissue/Cell Markers: Cre-lox System
  - Mutagenesis and Transgenesis: transcriptional activation
- Dermatology Research
- Cardiovascular Research
  - Cre-lox System
- Cre-lox System
  - loxP-flanked Sequences
- Developmental Biology Research
  - Cre-lox System
Cancer Research
- Growth Factors/Receptors/Cytokines
- Increased Tumor Incidence
  - Other Tissues/Organs: GI tract (stomach, intestine, colon)
Immunology, Inflammation and Autoimmunity Research
- Growth Factors/Receptors/Cytokines
- Intracellular Signaling Molecules
- Autoimmunity
Cell Biology Research
- Signal Transduction
Dermatology Research
- Other

Mammalian Phenotype Terms by Genotype

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

Genotype: Gt(ROSA)26Sor^{tm1(cre/ERT)Nat}/Gt(ROSA)26Sor⁺ Pdgfra^tm13Sor/Pdgfra⁺
involves: 129S4/SvJaeSor * C57BL/6

cardiovascular system phenotype

cardiac fibrosis
- in tamoxifen-treated mice

digestive/alimentary phenotype

intestinal fibrosis
- 4 of 9 tamoxifen-treated mice exhibit intestinal fibrosis

intestine polyps
- in one tamoxifen-treated mouse

integument phenotype

tight skin
- in some tamoxifen-treated mice

muscle phenotype

skeletal muscle interstitial fibrosis
- in tamoxifen-treated mice

renal/urinary system phenotype

glomerulosclerosis
- sclerotic glomeruli in tamoxifen-treated mice

renal glomerulus hypertrophy
- enlarged glomeruli in tamoxifen-treated mice

References

Olson LE ; Soriano P. 2009. Increased PDGFRalpha activation disrupts connective tissue development and drives systemic fibrosis. Dev Cell 16(2):303-13PubMed: 19217431 MGI: J:146617

Additional - Pdgfra^tm13Sor related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Pyrosequencing:** Pdgfra*V561D-alternate1
- Separated PCR:Pdgfra
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, heterozygous mice may be bred to wildtype mice from the colony. Homozygous mice die during embryonic development.
- Additional Breeding and Husbandry Support
Citation
When using the STOCK Pdgfra^tm13Sor/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #018432 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

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

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Heterozygous or Wildtype for Pdgfra<tm13Sor>

Payment Terms and Conditions

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

Terms Of Use

General Terms and Conditions

Questions about Terms of Use

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Licensing Information

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Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Approximate Controls

Additional Information

Selected References

Pdgfratm13Sor

Allele Symbol: Pdgfratm13Sor

Disease Terms

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Gt(ROSA)26Sortm1(cre/ERT)Nat/Gt(ROSA)26Sor+ Pdgfratm13Sor/Pdgfra+involves: 129S4/SvJaeSor * C57BL/6

cardiovascular system phenotype

digestive/alimentary phenotype

integument phenotype

muscle phenotype

renal/urinary system phenotype

References

Additional - Pdgfratm13Sor 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

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Pdgfra^tm13Sor

Allele Symbol: Pdgfra^tm13Sor

Genotype: Gt(ROSA)26Sor^{tm1(cre/ERT)Nat}/Gt(ROSA)26Sor⁺ Pdgfra^tm13Sor/Pdgfra⁺
involves: 129S4/SvJaeSor * C57BL/6

Additional - Pdgfra^tm13Sor related