Strain Detail Sheet

Strain Name    :

B6;129S4-Ptpn11tm1Bgn/Mmjax

Stock Number :

032104-JAX

Gene Information

Gene Details [Including genotyping protocols]

(provided by MGI)
Allele Symbol: Ptpn11tm1Bgn
Name: targeted mutation 1, Benjamin G Neel
Alteration at locus: Targeted Mutation
Gene Symbol: Ptpn11
Name: protein tyrosine phosphatase, non-receptor type 11
Chromosome: 5
Alteration at locus: Targeted Mutation

Genetic Alterations:

Genotype Determination:

ES Cell Line: J1 derived from B6;129S4

Strain Description [Including phenotype, strain background, strain development and suggested control mice]

Phenotype

Homozygous phenotype: No homozygous mice are born, however, 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.

Heterozygous phenotype: Mice that are heterozygous for the targeted mutation are born at 50% less than predicted Mendelian ratios. 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.


Mammalian Phenotype Terms:(provided by MGI)      Extend all MPTs
      assigned by genotype
Ptpn11tm1Bgn/Ptpn11+
        involves: 129S4/SvJae * C57BL/6
  • mortality/aging
    • partial perinatal lethality (MGI Ref ID J:147154)
      • about 50% of mice die either in late gestation or perinatally
      • penetrance of lethality is decreased compared to mice on a congenic C57BL/6 background
  • cardiovascular system phenotype
    • abnormal cardiac epithelial to mesenchymal transition (MGI Ref ID J:147154)
      • from 24 - 48 hours in culture endocardial cushions from E9.5 embryos give rise to more mesenchymal cells compared to wild-type controls
      • expression analysis indicates that enhanced production of mesenchymal cells is due to a prolongation of the normal interval during which EMT occurs
  • growth/size 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 (MGI Ref ID J:147154)
      • increase in the number of CFU-GM in the absence of cytokines compared to wild-type controls
  • vision/eye phenotype
    • ocular hypertelorism (MGI Ref ID J:147154)
      • increased inner canthal distance
Ptpn11 tm1Bgn/Ptpn11+
        involves: 129S4/SvJae * C57BL/6J
  • mortality/aging
    • partial perinatal lethality (MGI Ref ID J:91609)
      • at E18.5 some heterozygous embryos are dead and about 50% fewer than expected heterozygotes are found at weaning
  • cardiovascular system phenotype
    • abnormal heart development (MGI Ref ID J:91609)
      • enlarged atrioventricular valve primordia are seen in about 50% of heterozygotes (severely affected mutants)
    • decreased cardiomyocyte apoptosis (MGI Ref ID J:91609)
      • decreased apoptosis is seen in endocardial cushions from some heterozygous mutants
    • double outlet heart right ventricle (MGI Ref ID J:91609)
      • double outlet right ventricle is seen in about 50% of heterozygotes (severely affected mutants)
    • enlarged mitral valve (MGI Ref ID J:91609)
      • enlarged mitral valves are seen in about 50% of heterozygotes (not severely affected) at E13.5 but not at E18.5
    • ventricular septal defect (MGI Ref ID J:91609)
      • at E13.5 ventricular septal defects are seen in about 50% of heterozygotes (severely affected mutants)
  • cellular phenotype
    • increased cell proliferation (MGI Ref ID J:91609)
      • increased cellular proliferation is seen in endocardial cushions from some heterozygous mutants
  • craniofacial phenotype
    • abnormal snout morphology (MGI Ref ID J:91609)
      • a wider and blunter snout shape is seen
    • small cranium (MGI Ref ID J:91609)
      • 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
  • growth/size phenotype
    • decreased body length (MGI Ref ID J:91609)
      • a significant reduction in body weight and length is seen without altering overall body proportions
    • decreased body weight (MGI Ref ID J:91609)
      • a significant reduction in body weight and length is seen without altering overall body proportions
  • hematopoietic system phenotype
    • enlarged spleen (MGI Ref ID J:91609)
      • older heterozygotes develop splenomegaly with mild myeloid and erythroid hyperplasia
    • increased leukocyte cell number (MGI Ref ID J:91609)
      • by 5 months heterozygotes develop mild leukocytosis with normal hematocrit and platelet counts
      • increased lymphocyte cell number (MGI Ref ID J:91609)
      • increased neutrophil cell number (MGI Ref ID J:91609)
    • myeloid hyperplasia (MGI Ref ID J:91609)
      • mild myeloid hyperplasia is seen in the bone marrow of older heterozygotes
  • immune system phenotype
    • enlarged spleen (MGI Ref ID J:91609)
      • older heterozygotes develop splenomegaly with mild myeloid and erythroid hyperplasia
    • increased leukocyte cell number (MGI Ref ID J:91609)
      • by 5 months heterozygotes develop mild leukocytosis with normal hematocrit and platelet counts
      • increased lymphocyte cell number (MGI Ref ID J:91609)
      • increased neutrophil cell number (MGI Ref ID J:91609)
    • myeloid hyperplasia (MGI Ref ID J:91609)
      • mild myeloid hyperplasia is seen in the bone marrow of older heterozygotes
  • liver/biliary system phenotype
    • hepatic necrosis (MGI Ref ID J:91609)
      • at E13.5 some heterozygotes display mild liver damage
  • skeleton phenotype
    • small cranium (MGI Ref ID J:91609)
      • 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
  • muscle phenotype
    • decreased cardiomyocyte apoptosis (MGI Ref ID J:91609)
      • decreased apoptosis is seen in endocardial cushions from some heterozygous mutants
Ptpn11tm1Bgn/Ptpn11tm1Bgn
        involves: 129S4/SvJae * C57BL/6J
  • mortality/aging
    • complete embryonic lethality during organogenesis (MGI Ref ID J:91609)
      • homozygous embryos die around E13.5
  • cardiovascular system phenotype
    • abnormal heart development (MGI Ref ID J:91609)
      • enlarged outflow tract and atrioventricular valve primordia are seen
    • atrial septal defect (MGI Ref ID J:91609 )
      • at E13.5 atrial septal defects are seen
    • atrioventricular septal defect (MGI Ref ID J:91609)
      • at E13.5 atrioventricular septal defects are seen
    • decreased cardiomyocyte apoptosis (MGI Ref ID J:91609)
      • decreased apoptosis is seen in endocardial cushions
    • double outlet heart right ventricle (MGI Ref ID J:91609)
    • hemorrhage (MGI Ref ID J:91609)
      • at E13.5 embryos are grossly hemorrhagic
    • pericardial effusion (MGI Ref ID J:91609)
      • pericardial effusions are seen
    • thin myocardium (MGI Ref ID J:91609)
      • the myocardium is markedly thinner compared to wild-type
    • thin myocardium compact layer (MGI Ref ID J:91609)
    • ventricular septal defect (MGI Ref ID J:91609)
      • at E13.5 ventricular and atrioventricular septal defects are seen
  • cellular phenotype
    • increased cell proliferation (MGI Ref ID J:91609)
      • increased cellular proliferation is seen in endocardial cushions
  • homeostasis/metabolism phenotype
    • hydrops fetalis (MGI Ref ID J:91609)
      • at E13.5 embryos are grossly edematous with pericardial and peritoneal effusions and subcutaneous edema
    • pericardial effusion (MGI Ref ID J:91609)
      • pericardial effusions are seen
  • liver/biliary system phenotype
    • hepatic necrosis (MGI Ref ID J:91609)
      • at E13.5 severe liver necrosis is seen
    • small liver (MGI Ref ID J:91609)
      • at E13.5 decreased liver size is seen
  • muscle phenotype
    • decreased cardiomyocyte apoptosis (MGI Ref ID J:91609)
      • decreased apoptosis is seen in endocardial cushions


The following phenotype information may relate to one or more alleles on a genetic background differing from this MMRRC strain.
Ptpn11tm1Bgn/Ptpn11+
        129S6.129S4-Ptpn11<tm1Bgn>
  • mortality/aging
    • mortality/aging (MGI Ref ID J:147154)
      • unlike mice on a congenic C57BL/6 background nearly all mice survive
Ptpn11tm1Bgn/Ptpn11+
        B6.129S4-Ptpn11<tm1Bgn>
  • mortality/aging
    • partial perinatal lethality (MGI Ref ID J:147154)
      • 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
      • almost all mice die
  • cardiovascular system phenotype
    • abnormal heart morphology (MGI Ref ID J:147154)
      • all mice show severe cardiac defects
Ptpn11tm1Bgn/Ptpn11+
        C.129S4-Ptpn11<tm1Bgn>
  • mortality/aging
    • partial perinatal lethality (MGI Ref ID J:147154)
      • about 50% of mice die either in late gestation or perinatally
      • penetrance of lethality is decreased compared to mice on a congenic C57BL/6 background

Strain of Origin: 129S4/SvJae

Strain genetic background: B6;129S4

Strain 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.

Suggested Control Mice: Wild-type littermates

Research Applications

  • Cardiovascular
  • Developmental Biology
  • Hematology
  • Models for Human Disease

Strain Origin

Donor: Benjamin G. Neel, MD PhD, Ontario Cancer Institute

Primary Reference:

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

Colony and Husbandry Information

Special Considerations

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

Health Status Report

Mice recovered from a cryo-archive will have health surveillance performed on recipient females. Health reports will be provided prior to shipment. If you require additional health status information, please email csmmrrc@jax.org.

Order Request Information

Availability Level

Limited quantities of breeder mice (recovered litter) are available from a cryoarchive; recovered litter usually available to ship in 3 to 4 months.

Conditions of Distribution [Including applicable technology transfer agreements]

Distribution of this strain requires submission of the MMRRC Conditions of Use (COU). A link to the COU web form will be provided via email after an order has been placed; the form should be completed then or the email forwarded to your institutional official for completion.

The donor or their institution limits the distribution to non-profit institutions only.

Fees

Additional charges may apply for any special requests. Shipping costs are in addition to the basic distribution/resuscitation fees. Information on shipping costs and any additional charges will be provided by the supplying MMRRC facility.

Click button to Request this one strain. (Use the MMRRC Catalog Search to request more than one strain.)
MMRRC Item # - Description Distribution
Fee/unit (US $)
Units Notes
032104-JAX-RESUSLitter recovered from cryo-archive
$2,022.00
Non-Profit
Litter Recovered litter1; additional fees for any special requests.
032104-JAX-SPERMCryo-preserved spermatozoa
$437.00
Non-Profit
Aliquot Approximate quantity.2

1 The distribution fee covers the expense of resuscitating mice from the cryo-archive; you will receive the resulting litter. The litter will contain at minimum one mutant carrier; the actual number of animals and the gender and genotype ratios will vary. (Typically, multiple breeder pairs can be established from the recovered litter.) Prior to shipment, the MMRRC will provide information about the animals recovered. If you anticipate or find that you need to request specific genotypes, genders or quantities of mice in excess of what is likely from a resuscitated litter, you may discuss available options and pricing with the supplying MMRRC facility.

2 An aliquot is one straw or vial with sufficient sperm to recover at least one litter of mice, as per provided protocols, when performed at the MMRRC facility. The MMRRC makes no guarantee concerning the success of these procedures when performed outside the MMRRC facilities.

3 An aliquot contains a sufficient number of embryos (in one or more vials and based on the transfer success rate of the MMRRC facility) to transfer to at least two recipients. The MMRRC makes no guarantee concerning embryo transfer success experienced in the recipient investigator's laboratory. Neither gender nor genotype ratios are guaranteed.

To request material from the MMRRC: Please fill out our on-line request form (accessible from the catalog search results page, or click the Request this Strain button in the fees section above). If you have questions or need assistance completing this form, you may call Customer Service at (800) 910-2291 (in USA or Canada) or (530) 757-5710 (international calls). Before you call, please have with you: the MMRRC item number, quantity needed, Bill-to and Ship-to contact information.



To request material from the MMRRC: Please fill out our on-line request form (accessible from the catalog search results page, or click the Request this Strain button in the fees section). If you have questions or need assistance completing this form, you may call Customer Service at (800) 910-2291 (in USA or Canada) or (530) 757-5710 (international calls). Before you call, please have with you: the MMRRC item number, quantity needed, Bill-to and Ship-to contact information.



The MMRRC is a collaborative effort, funded by grants from DPCPSI of the NIH.

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