Strain Name:
B6JNci.Cg-Wwp1tm1Lmat/Mmnc
Stock Number:
066735-UNC
Citation ID:
RRID:MMRRC_066735-UNC
Other Names:
B6 Wwp1-/-

Strain Information

Wwp1tm1Lmat
Name: WW domain containing E3 ubiquitin protein ligase 1; targeted mutation 1, Lydia E Matesic
Type: Allele
Species: Mus musculus (mouse)
Chromosome: 4
Alteration at locus: Knockout
Wwp1
Name: WW domain containing E3 ubiquitin protein ligase 1
Synonyms: 8030445B08Rik, Tiul1, SDRP1, AIP5
Type: Gene
Species: Mouse
Chromosome: 4
Alteration at locus: Knockout
NCBI: 107568
Homologene: 21385
Genetic Alterations
Replacement of exons 10-20 of the Wwp1 gene with a floxed Neo creates an in-frame deletion of the the WWP1 protein which removes the WW domains and the 5' half of the HECT domain, rendering it a functional null.
Genotype Determination
  • Genotyping Protocol(s)
  • Center protocol and contact for technical support will be shipped with mice.
  • ES Cell Line
    CJ7
    Phenotype
    Overall, homozygous knockout animals are viable and fertile. However, the targeted examination of these animals has revealed some phenotypic variation. The published phenotypes of this mouse (a constitutive knockout of Wwp1) include:

    1. In PMID:31097636 -- homozygous knockout animals were found to have overall smaller body weight and size as compared to gender-matched wild-type littermate controls. These animals were also demonstrated to be resistant to the development of prostate tumors when crossed to the Hi-Myc mouse model, manifesting as a significant reduction in tumor size, weight, invasiveness, and tumor cell proliferation. Molecularly, it was determined that this was due, in part, to the K27 polyubiquitination of PTEN by WWP1, which inhibited the dimerization, membrane recruitment, and phosphatase function of PTEN, causing activation of the PI3K-AKT-mTOR axis.
    2. In PMID:23553732 -- homozygous knockout animals were protected from age-associated bone loss due to the increased bone mass from larger numbers of bone marrow stromal cells committing to and differentiating along the osteoblast lineage as compared to those derived from wild type littermates. Though differences in trabecular bone volume were apparent as early as one month of age, the differences became more pronounced in older animals (i.e., 6-12 months of age). Molecularly, this was accounted for by the stabilization of the transcription factor JunB in cells derived from Wwp1-/- mice.
    3. In PMID:21809421 -- mesenchymal stem cells derived from the stroma of the bone marrow of Wwp1-/- mice had more osteogenic potential as well as rescued these cells from the inhibitory effects of TNF (similar to what is observed in inflammatory osteoporosis) as compared to Wwp1+/+ littermates. The donor is preparing a manuscript that more clearly spells out the targeting strategy and demonstrates that loss of WWP1 causes increased amounts of Cx43 to localize to the intercalated discs in cardiomyocytes while another shows that these knockout mice have an attenuated response to pressure overload created via TAC (transaortic constriction).
    MeSH Terms
    • Anticarcinogenic Agents/pharmacology
    • Anticarcinogenic Agents/therapeutic use
    • Carcinogenesis/drug effects
    • HEK293 Cells
    • Humans
    • Indoles/pharmacology
    • Indoles/therapeutic use
    • Male
    • Neoplasms/drug therapy
    • Neoplasms/metabolism
    • PTEN Phosphohydrolase/genetics
    • PTEN Phosphohydrolase/metabolism
    • Protein Multimerization
    • Proto-Oncogene Proteins c-myc/antagonists & inhibitors
    • Proto-Oncogene Proteins c-myc/genetics
    • Tumor Suppressor Proteins/genetics
    • Tumor Suppressor Proteins/metabolism
    • Ubiquitin-Protein Ligases/antagonists & inhibitors
    • Ubiquitin-Protein Ligases/genetics
    • Ubiquitination/drug effects
    • Animals
    • Cell Differentiation
    • Cells, Cultured
    • Chondrogenesis
    • Core Binding Factor Alpha 1 Subunit/genetics
    • Core Binding Factor Alpha 1 Subunit/metabolism
    • Gene Knockdown Techniques
    • Leukocyte Common Antigens/metabolism
    • Mesenchymal Stem Cells/cytology
    • Mesenchymal Stem Cells/metabolism
    • Mice
    • Mice, Inbred C57BL
    • Mice, Transgenic
    • Osteoblasts/cytology
    • Osteoblasts/metabolism
    • Osteogenesis
    • Plasmids/genetics
    • Plasmids/metabolism
    • Proto-Oncogene Proteins c-jun/genetics
    • Proto-Oncogene Proteins c-jun/metabolism
    • RNA, Small Interfering/genetics
    • RNA, Small Interfering/metabolism
    • Transcription Factor AP-1/genetics
    • Transcription Factor AP-1/metabolism
    • Transfection
    • Tumor Necrosis Factor-alpha/genetics
    • Tumor Necrosis Factor-alpha/metabolism
    • Ubiquitin-Protein Ligases/metabolism
    • Ubiquitination
    • Aging
    • Cell Differentiation/drug effects
    • Cell Movement/drug effects
    • Chemokine CXCL12/pharmacology
    • Mesenchymal Stem Cells/drug effects
    • Organ Size/drug effects
    • Osteoblasts/enzymology
    • Osteogenesis/drug effects
    • Proteolysis/drug effects
    • Receptors, CXCR4/metabolism
    • Transcription Factors/metabolism
    • Ubiquitin-Protein Ligases/deficiency
    Strain Development
    Targeting vector contained DNA flanking exons 10-20, replacing with a Neo. Electroporation of linearized targeting vector into CJ7 ES cells (origin 129S1/SvImJ). G418 selection, clonal expansion, and screening of 113 colonies via Southern for correct targeting into the Wwp1 locus. Single, targeted ES clone injected into C57BL/6J host blastocysts to produce chimeras. Southern blot to confirm the genotype of chimeras. Mating of chimera offspring with C57BL/6JNci for germline transmission. Offspring genotyped by both Southern and by PCR on tail snip DNA. Backcrossed to C57BL/6JNci for 12 generations then heterozygous knockouts were intercrossed to generate a homozygous line. Homozygous-by-homozygous intercrosses used to maintain the line to F19 at the time of the donation to the MMRRC.

    Note: The NeoR cassette is still present. The line was never exposed to Cre.
    Suggested Control Mice
    C57BL/6J
    MMRRC Genetic QC Summary
    The MMRRC Centers have developed a genetic QC pipeline using MiniMUGA array genotyping to provide additional information on strain backgrounds for MMRRC congenic and inbred strains. For more information on when data may be available, or to request genotyping for a strain of interest, please contact mmrrc@med.unc.edu. Older strains may not have this information.
    • Cancer
    • Cardiovascular
    • Developmental Biology
    • Hematology
    • Immunology and Inflammation
    • Metabolism
    • Models for Human Disease
    • Neurobiology
    • Virology
    Donor
    Lino Tessarollo, Ph.D., National Cancer Institute.
    Lydia Matesic, Ph.D., University of South Carolina.
    Neal Copeland, Ph.D., The University of Texas MD Anderson Cancer Center.
    Nancy Jenkins, Ph.D., Houston Methodist - Weill Cornell Medical College.
    Primary Reference

    Lee YR, Chen M, Lee JD, Zhang J, Lin SY, Fu TM, Chen H, Ishikawa T, Chiang SY,Katon J, Zhang Y, Shulga YV, Bester AC, Fung J, Monteleone E, Wan L, Shen C, Hsu CH, Papa A, Clohessy JG, Teruya-Feldstein J, Jain S, Wu H, Matesic L, Chen RH,Wei W, Pandolfi PP. Reactivation of PTEN tumor suppressor for cancer treatmentthrough inhibition of a MYC-WWP1 inhibitory pathway. Science. 2019 May17;364(6441). pii: eaau0159. doi: 10.1126/science.aau0159. (Medline PMID: 31097636)

    Zhao L, Huang J, Zhang H, Wang Y, Matesic LE, Takahata M, Awad H, Chen D, XingL. Tumor necrosis factor inhibits mesenchymal stem cell differentiation intoosteoblasts via the ubiquitin E3 ligase Wwp1. Stem Cells. 2011Oct;29(10):1601-10. doi: 10.1002/stem.703. (Medline PMID: 21809421)

    Shu L, Zhang H, Boyce BF, Xing L. Ubiquitin E3 ligase Wwp1 negativelyregulates osteoblast function by inhibiting osteoblast differentiation andmigration. J Bone Miner Res. 2013 Sep;28(9):1925-35. doi: 10.1002/jbmr.1938.(Medline PMID: 23553732)

    Colony and Husbandry Information

    Colony Surveillance Program and Current Health Reports

    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 mmrrc_health@med.unc.edu.
    Coat Color
    Black
    Eye
    Black
    MMRRC Breeding System
    Backcross then random intra-strain mating
    Generation
    N12 (C57BL/6JNci), F19
    Overall Breeding Performance
    Good
    Viability and Fertility: Female Male Comments
    Homozygotes are viable: Yes Yes
    Homozygotes are fertile: Yes Yes
    Heterozygotes are fertile: Yes Yes
    Age Reproductive Decline: 7 to 9 months 7 to 9 months
    Bred to Homozygosity
    Yes
    Average litter size
    7 to 9
    Recommended wean age
    3 Weeks
    Average Pups Weaned
    7 to 9

    Order Request Information

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

    Cryopreserved material may be available upon request, please inquire to mmrrc@med.unc.edu for more information.

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

    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.

    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 $)
    *Shipping & Handling not included*
    Units Notes
    066735-UNC-RESUS Litter recovered from cryo-archive $2,914.00 / Non-Profit Litter Recovered litter4; additional fees for any special requests.
    Cryopreserved material may be available upon request, please inquire to mmrrc@med.unc.edu for more information.

    1 The distribution fee covers the expense of rederiving mice from a live mouse; 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 contains a sufficient number of embryos (in one or more vials or straws and based on the transfer success rate of the MMRRC facility) to transfer into one to three recipients. The MMRRC makes no guarantee concerning embryo transfer success experienced in the recipient investigator's laboratory. Neither gender nor genotype ratios are guaranteed.

    3 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.

    4 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.

    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.