Strain Name:

B6;129S4-Ptpn11tm1Bgn/Mmjax

Availability:

Cryopreserved - Ready for recovery     Available at the JAX MMRRC

Please refer to the Mutant Mouse Regional Resource Center (MMRRC) for information about B6;129S4-Ptpn11tm1Bgn/Mmjax MMRRC Stock Number 032104.
Mice heterozygous for the Ptpn11D61G allele are born at 50% less than predicted Mendelian ratios for a het x het mating. Surviving heterozygotes are characterized by a decreased body size, a triangular facial appearance and multiple cardiac defects. By 5 months, heterozygotes develop leukocytosis, splenomegaly and a mild myeloproliferative disease. This mutant mouse strain may be useful in studies of Noonan syndrome.

Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Mutant Stock; Targeted Mutation;
Additional information on Genetically Engineered and Mutant Mice.
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Specieslaboratory mouse
Generation+pN1
Generation Definitions
 
Donating Investigator Benjamin Neel,   Ontario Cancer Institute

Description
Mice that are heterozygous for the targeted mutation are born at 50% less than predicted Mendelian ratios for a heterozygote x heterozygote mating. No homozygous mice are born. At E11.5 all genotypes are represented at normal ratios, but by E13.5 homozygous embryos are reduced in number, have multiple cardiac defects and are grossly hemorrhagic with severe liver necrosis. Among E13.5 heterozygotes, 50% exhibit ventricular septal defects and enlarged valve primordia, but without myocardial thinning or edema and 50% exhibit mitral valve enlargement with normal hearts. Surviving heterozygotes reach at least 10 months of age. Similar to Noonan patients, heterozygous mice are characterized by a decreased body size and a triangular facial appearance. By 5 months, heterozygotes develop leukocytosis, splenomegaly and a mild myeloproliferative disease. This mutant mouse strain may be useful in studies of Noonan syndrome.

Development
The targeting vector was designed (by site-directed mutagenesis) to change the Noonan syndrome associated mutation from aspartate to glycine at amino acid position 61 (D61G) and to insert a unique AgeI site in exon 3. A loxP-flanked pGK neomycin cassette was also inserted downstream of exon 3. The construct was electroporated into 129S4/SvJae derived J1 embryonic stem (ES) cells. Transient Cre expression in targeted cells excised the neo cassette. Correctly targeted ES cells were injected into blastocysts. The resulting chimeric animals were crossed to C57BL/6 mice and maintained as sibling matings. Upon arrival, mice were bred to C57BL/6 for at 1 generation to establish the colony.

Control Information

  Control
   101045 B6129SF2/J (approximate)
 
  Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Ptpn11
012591   B6.129S4-Ptpn11tm1Yan/Mmjax
012592   B6.129S6-Ptpn11tm1Toa/Mmjax
View Strains carrying other alleles of Ptpn11     (2 strains)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI
- 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).
Noonan Syndrome 1; NS1
- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested.
Juvenile Myelomonocytic Leukemia; JMML   (PTPN11)
Leopard Syndrome 1   (PTPN11)
Metachondromatosis; METCDS   (PTPN11)
View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI
      assigned by genotype

Ptpn11tm1Bgn/Ptpn11+

        involves: 129S4/SvJae * C57BL/6J
  • mortality/aging
  • partial perinatal lethality
    • at E18.5 some heterozygous embryos are dead and about 50% fewer than expected heterozygotes are found at weaning   (MGI Ref ID J:91609)
  • cardiovascular system phenotype
  • abnormal heart development
    • enlarged atrioventricular valve primordia are seen in about 50% of heterozygotes (severely affected mutants)   (MGI Ref ID J:91609)
  • decreased cardiomyocyte apoptosis
    • decreased apoptosis is seen in endocardial cushions from some heterozygous mutants   (MGI Ref ID J:91609)
  • double outlet right ventricle
    • double outlet right ventricle is seen in about 50% of heterozygotes (severely affected mutants)   (MGI Ref ID J:91609)
  • enlarged mitral valve
    • enlarged mitral valves are seen in about 50% of heterozygotes (not severely affected) at E13.5 but not at E18.5   (MGI Ref ID J:91609)
  • ventricular septal defect
    • at E13.5 ventricular septal defects are seen in about 50% of heterozygotes (severely affected mutants)   (MGI Ref ID J:91609)
  • cellular phenotype
  • decreased cardiomyocyte apoptosis
    • decreased apoptosis is seen in endocardial cushions from some heterozygous mutants   (MGI Ref ID J:91609)
  • increased cell proliferation
    • increased cellular proliferation is seen in endocardial cushions from some heterozygous mutants   (MGI Ref ID J:91609)
  • craniofacial phenotype
  • abnormal snout morphology
    • a wider and blunter snout shape is seen   (MGI Ref ID J:91609)
  • small cranium
    • consistent with the decreased body size the skull is smaller than normal however width is not different from wild-type resulting in a greater length/width ratio   (MGI Ref ID J:91609)
  • growth/size/body phenotype
  • abnormal snout morphology
    • a wider and blunter snout shape is seen   (MGI Ref ID J:91609)
  • decreased body length
    • a significant reduction in body weight and length is seen without altering overall body proportions   (MGI Ref ID J:91609)
  • decreased body weight
    • a significant reduction in body weight and length is seen without altering overall body proportions   (MGI Ref ID J:91609)
  • hematopoietic system phenotype
  • enlarged spleen
    • older heterozygotes develop splenomegaly with mild myeloid and erythroid hyperplasia   (MGI Ref ID J:91609)
  • increased leukocyte cell number
    • by 5 months heterozygotes develop mild leukocytosis with normal hematocrit and platelet counts   (MGI Ref ID J:91609)
    • increased lymphocyte cell number   (MGI Ref ID J:91609)
    • increased neutrophil cell number   (MGI Ref ID J:91609)
  • myeloid hyperplasia
    • mild myeloid hyperplasia is seen in the bone marrow of older heterozygotes   (MGI Ref ID J:91609)
  • immune system phenotype
  • enlarged spleen
    • older heterozygotes develop splenomegaly with mild myeloid and erythroid hyperplasia   (MGI Ref ID J:91609)
  • increased leukocyte cell number
    • by 5 months heterozygotes develop mild leukocytosis with normal hematocrit and platelet counts   (MGI Ref ID J:91609)
    • increased lymphocyte cell number   (MGI Ref ID J:91609)
    • increased neutrophil cell number   (MGI Ref ID J:91609)
  • myeloid hyperplasia
    • mild myeloid hyperplasia is seen in the bone marrow of older heterozygotes   (MGI Ref ID J:91609)
  • liver/biliary system phenotype
  • hepatic necrosis
    • at E13.5 some heterozygotes display mild liver damage   (MGI Ref ID J:91609)
  • skeleton phenotype
  • small cranium
    • consistent with the decreased body size the skull is smaller than normal however width is not different from wild-type resulting in a greater length/width ratio   (MGI Ref ID J:91609)
  • muscle phenotype
  • decreased cardiomyocyte apoptosis
    • decreased apoptosis is seen in endocardial cushions from some heterozygous mutants   (MGI Ref ID J:91609)

Ptpn11tm1Bgn/Ptpn11+

        involves: 129S4/SvJae * C57BL/6
  • mortality/aging
  • partial perinatal lethality
    • about 50% of mice die either in late gestation or perinatally   (MGI Ref ID J:147154)
    • penetrance of lethality is decreased compared to mice on a congenic C57BL/6 background   (MGI Ref ID J:147154)
  • cardiovascular system phenotype
  • abnormal cardiac epithelial to mesenchymal transition
    • from 24 - 48 hours in culture endocardial cushions from E9.5 embryos give rise to more mesenchymal cells compared to wild-type controls   (MGI Ref ID J:147154)
    • expression analysis indicates that enhanced production of mesenchymal cells is due to a prolongation of the normal interval during which EMT occurs   (MGI Ref ID J:147154)
  • growth/size/body phenotype
  • decreased body length   (MGI Ref ID J:147154)
  • decreased body weight   (MGI Ref ID J:147154)
  • hematopoietic system phenotype
  • abnormal common myeloid progenitor cell morphology
    • increase in the number of CFU-GM in the absence of cytokines compared to wild-type controls   (MGI Ref ID J:147154)
  • vision/eye phenotype
  • ocular hypertelorism
    • increased inner canthal distance   (MGI Ref ID J:147154)

Ptpn11tm1Bgn/Ptpn11tm1Bgn

        involves: 129S4/SvJae * C57BL/6J
  • mortality/aging
  • complete embryonic lethality during organogenesis
    • homozygous embryos die around E13.5   (MGI Ref ID J:91609)
  • cardiovascular system phenotype
  • abnormal heart development
    • enlarged outflow tract and atrioventricular valve primordia are seen   (MGI Ref ID J:91609)
  • atrial septal defect
    • at E13.5 atrial septal defects are seen   (MGI Ref ID J:91609)
  • atrioventricular septal defect
    • at E13.5 atrioventricular septal defects are seen   (MGI Ref ID J:91609)
  • decreased cardiomyocyte apoptosis
    • decreased apoptosis is seen in endocardial cushions   (MGI Ref ID J:91609)
  • double outlet right ventricle   (MGI Ref ID J:91609)
  • hemorrhage
    • at E13.5 embryos are grossly hemorrhagic   (MGI Ref ID J:91609)
  • pericardial effusion
    • pericardial effusions are seen   (MGI Ref ID J:91609)
  • thin myocardium compact layer   (MGI Ref ID J:91609)
  • thin myocardium
    • the myocardium is markedly thinner compared to wild-type   (MGI Ref ID J:91609)
  • ventricular septal defect
    • at E13.5 ventricular and atrioventricular septal defects are seen   (MGI Ref ID J:91609)
  • cellular phenotype
  • decreased cardiomyocyte apoptosis
    • decreased apoptosis is seen in endocardial cushions   (MGI Ref ID J:91609)
  • increased cell proliferation
    • increased cellular proliferation is seen in endocardial cushions   (MGI Ref ID J:91609)
  • homeostasis/metabolism phenotype
  • hydrops fetalis
    • at E13.5 embryos are grossly edematous with pericardial and peritoneal effusions and subcutaneous edema   (MGI Ref ID J:91609)
  • pericardial effusion
    • pericardial effusions are seen   (MGI Ref ID J:91609)
  • liver/biliary system phenotype
  • hepatic necrosis
    • at E13.5 severe liver necrosis is seen   (MGI Ref ID J:91609)
  • small liver
    • at E13.5 decreased liver size is seen   (MGI Ref ID J:91609)
  • muscle phenotype
  • decreased cardiomyocyte apoptosis
    • decreased apoptosis is seen in endocardial cushions   (MGI Ref ID J:91609)

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

Ptpn11tm1Bgn/Ptpn11+

        C.129S4-Ptpn11tm1Bgn
  • mortality/aging
  • partial perinatal lethality
    • about 50% of mice die either in late gestation or perinatally   (MGI Ref ID J:147154)
    • penetrance of lethality is decreased compared to mice on a congenic C57BL/6 background   (MGI Ref ID J:147154)

Ptpn11tm1Bgn/Ptpn11+

        B6.129S4-Ptpn11tm1Bgn
  • mortality/aging
  • partial perinatal lethality
    • penetrance of lethality is increased compared to mice on a 129S6/SvEv or BALB/c congenic background and to mice on a mixed 129S4/SvJae and C57BL/6 background   (MGI Ref ID J:147154)
    • almost all mice die   (MGI Ref ID J:147154)
  • cardiovascular system phenotype
  • abnormal heart morphology
    • all mice show severe cardiac defects   (MGI Ref ID J:147154)

Ptpn11tm1Bgn/Ptpn11+

        129S6.129S4-Ptpn11tm1Bgn
  • mortality/aging
  • *normal* mortality/aging
    • unlike mice on a congenic C57BL/6 background nearly all mice survive   (MGI Ref ID J:147154)
View Research Applications

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

Cardiovascular Research
Heart Abnormalities

Developmental Biology Research
Craniofacial and Palate Defects
Embryonic Lethality (Homozygous)
Internal/Organ Defects
      liver

Hematological Research
Hematopoietic Defects

Immunology, Inflammation and Autoimmunity Research
Inflammation
      Neutrophil defects
Lymphoid Tissue Defects
      myeloid hyperplasia

Internal/Organ Research
Liver Defects

Genes & Alleles

Gene & Allele Information provided by MGI

 
Allele Symbol Ptpn11tm1Bgn
Allele Name targeted mutation 1, Benjamin G Neel
Allele Type Targeted
Common Name(s) Ptpn11D61G;
Mutation Made By Benjamin Neel,   Ontario Cancer Institute
Strain of Origin129S4/SvJae
Promoter Ptpn11, protein tyrosine phosphatase, non-receptor type 11, mouse, laboratory
Molecular Note A D61G mutation was introduced into exon 3 by homologous recombination, as well as a floxed PGK-neo in intron 3. Transient Cre expression excised the neo, leaving the aspartate to glycine codon substitution. Southern blotting confirmed recombination and Western blotting indicated that expression of the mutant allele was normal. [MGI Ref ID J:91609]

Genotyping

Genotyping Information

Genotyping Protocols

Ptpn11 (exon 3), Sanger sequencing


Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Araki T; Mohi MG; Ismat FA; Bronson RT; Williams IR; Kutok JL; Yang W; Pao LI; Gilliland DG; Epstein JA; Neel BG. 2004. Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation. Nat Med 10(8):849-57. [PubMed: 15273746]  [MGI Ref ID J:91609]

Additional References

Ptpn11tm1Bgn related

Araki T; Chan G; Newbigging S; Morikawa L; Bronson RT; Neel BG. 2009. Noonan syndrome cardiac defects are caused by PTPN11 acting in endocardium to enhance endocardial-mesenchymal transformation. Proc Natl Acad Sci U S A 106(12):4736-41. [PubMed: 19251646]  [MGI Ref ID J:147154]

Brouillard P; Boon L; Vikkula M. 2014. Genetics of lymphatic anomalies. J Clin Invest 124(3):898-904. [PubMed: 24590274]  [MGI Ref ID J:209628]

Eminaga S; Bennett AM. 2008. Noonan syndrome-associated SHP-2/Ptpn11 mutants enhance SIRPalpha and PZR tyrosyl phosphorylation and promote adhesion-mediated ERK activation. J Biol Chem 283(22):15328-38. [PubMed: 18378677]  [MGI Ref ID J:137570]

Serra-Nedelec Ade R; Edouard T; Treguer K; Tajan M; Araki T; Dance M; Mus M; Montagner A; Tauber M; Salles JP; Valet P; Neel BG; Raynal P; Yart A. 2012. Noonan syndrome-causing SHP2 mutants inhibit insulin-like growth factor 1 release via growth hormone-induced ERK hyperactivation, which contributes to short stature. Proc Natl Acad Sci U S A 109(11):4257-62. [PubMed: 22371576]  [MGI Ref ID J:182238]

Wang S; Yu WM; Zhang W; McCrae KR; Neel BG; Qu CK. 2009. Noonan syndrome/leukemia-associated gain-of-function mutations in SHP-2 phosphatase (PTPN11) enhance cell migration and angiogenesis. J Biol Chem 284(2):913-20. [PubMed: 19008228]  [MGI Ref ID J:145564]

Xu D; Wang S; Yu WM; Chan G; Araki T; Bunting KD; Neel BG; Qu CK. 2010. A germline gain-of-function mutation in Ptpn11 (Shp-2) phosphatase induces myeloproliferative disease by aberrant activation of hematopoietic stem cells. Blood 116(18):3611-21. [PubMed: 20651068]  [MGI Ref ID J:166477]

Xu D; Zheng H; Yu WM; Qu CK. 2013. Activating mutations in protein tyrosine phosphatase Ptpn11 (Shp2) enhance reactive oxygen species production that contributes to myeloproliferative disorder. PLoS One 8(5):e63152. [PubMed: 23675459]  [MGI Ref ID J:202176]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Animal Health Reports

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

Colony Maintenance

Breeding & HusbandryWhile maintaining a live colony, these mice are bred as heterozygotes. Mice homozygous for the mutation are not viable.

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