Strain Name:

B6.129S4-Timp2tm1Pds/J

Stock Number:

008120

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These mice are deficient in TIMP-2, tissue inhibitor of metalloproteinase 2, and exhibit locomotor impairment, abnormal fear conditioning behavior, and defective neuronal differentiation. This mutant mouse strain may be useful in studies of extracellular matrix homeostasis, synaptic plasticity in behavior, learning and memory, neuronal differentiation and development of neuromuscular junctions.

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 Congenic; Mutant Strain; Targeted Mutation;
Additional information on Genetically Engineered and Mutant Mice.
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Additional information on Congenic nomenclature.
Specieslaboratory mouse
 
Donating Investigator Paul D. Soloway,   Cornell University

Description
Mice that are homozygous for the targeted mutation are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. No gene product (mRNA) is detected by Northern blot analysis of lung tissue. Mutant mice are unable to proteolytically activate proMMP-2, proenzyme matrix metalloproteinase-2. Male homozygotes exhibit deficits in fear-potentiated startle respnses and both male and female mutants exhibit reduced prepulse inhibition. Homozygotes exhibit muscle weakness (due to reduced mass of extensor digitorum longus fast-twitch muscle), decreased motor function, abnormal gait and reduced hindlimb extension. The brains of homozygotes in the postnatal week are smaller in size than wildtype controls, with the size difference disappearing after postnatal day 7. Histological analysis reveals abnormal neuromuscular junctions characterized by a larger size with increased nerve branching, reduced cerebellar cortex thickness, and reduced Purkinje cell processes. Homozygotes have impaired neuronal differentiation. Female homozygotes are passive when handled, while male homozygotes are aggressive. This mutant mouse strain may be useful in studies of extracellular matrix homeostasis, synaptic plasticity in behavior, learning and memory, neuronal differentiation and development of neuromuscular junctions.

Development
A targeting vector containing PGKneo cassette was used to disrupt exon 1 and 5' flanking sequence. The construct was electroporated into 129S4/SvJae derived J1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. The resulting chimeric animals were crossed to generate homozygous mice. The mice were then backcrossed to C57BL/6 J for 12 generations before arriving at The Jackson Laboratory.

Control Information

  Control
   000664 C57BL/6J
 
  Considerations for Choosing Controls

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI
      assigned by genotype

Timp2tm1Pds/Timp2tm1Pds

        B6.129S4-Timp2tm1Pds
  • behavior/neurological phenotype
  • abnormal cued conditioning behavior
    • null mice have a deficit in fear-potentiated startle (FPS) vs wild-type; mice generate greater startle responses compared to wild-type mice in presence of tone before fear conditioning (ie. P0 - first testing session)   (MGI Ref ID J:99752)
    • all males show an increase in FPS initially (from P0 to P1) but FPS decreases from that point in knockout and knockdown mice; in wild-type and heterozygotes, amplitudes of startle responses continue to increase   (MGI Ref ID J:99752)
    • wild-type and heterozygous males acquire conditioned fear over the course of the test, but null and knockdown mice do not   (MGI Ref ID J:99752)
    • females do not show any proportional increases in FPS   (MGI Ref ID J:99752)
  • nervous system phenotype
  • decreased prepulse inhibition
    • Timp2-null mice have significantly reduced prepulse inhibition (PPI)   (MGI Ref ID J:99752)

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

Timp2tm1Pds/Timp2tm1Pds

        involves: 129S4/SvJae * C57BL/6
  • hematopoietic system phenotype
  • increased neutrophil cell number
    • at day 7 after treatment, BAL neutrophil percentage and concentration are 3- and 10-fold higher in Timp1-null mice compared to Timp2-null animals; values for Timp2-null mice are similar to wild-type   (MGI Ref ID J:112941)
  • immune system phenotype
  • increased neutrophil cell number
    • at day 7 after treatment, BAL neutrophil percentage and concentration are 3- and 10-fold higher in Timp1-null mice compared to Timp2-null animals; values for Timp2-null mice are similar to wild-type   (MGI Ref ID J:112941)
  • homeostasis/metabolism phenotype
  • abnormal enzyme/coenzyme activity
    • activation of proMMP-2 in vivo is dramatically altered with Timp2 deficiency   (MGI Ref ID J:64001)
  • cardiovascular system phenotype
  • *normal* cardiovascular system phenotype
    • following angiotensin II infusion, mice exhibit a normal increase in blood pressure and normal heart rate   (MGI Ref ID J:211441)
View Research Applications

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

Cell Biology Research
Defects in Extracellular Matrix Molecules

Developmental Biology Research
Defects in Extracellular Matrix Molecules
Neurodevelopmental Defects

Neurobiology Research
Ataxia (Movement) Defects
Behavioral and Learning Defects
Cerebellar Defects
      Purkinje cell defect
Neurodevelopmental Defects
Neuromuscular Defects

Genes & Alleles

Gene & Allele Information provided by MGI

 
Allele Symbol Timp2tm1Pds
Allele Name targeted mutation 1, Paul D Soloway
Allele Type Targeted (Null/Knockout)
Common Name(s) TIMP-2KO; TIMP2KO; Timp2-;
Mutation Made By Paul Soloway,   Cornell University
Strain of Origin129S4/SvJae
ES Cell Line NameJ1
ES Cell Line Strain129S4/SvJae
Gene Symbol and Name Timp2, tissue inhibitor of metalloproteinase 2
Chromosome 11
Gene Common Name(s) CSC-21K; D11Bwg1104e; DDC8; DNA segment, Chr 11, Brigham & Women's Genetics 1104 expressed; TIMP-2; Timp-2;
Molecular Note Replacement of the first coding exon with a neomycin cassette. [MGI Ref ID J:64001]

Genotyping

Genotyping Information

Genotyping Protocols

Timp2tm1Pds, Standard PCR


Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Wang Z; Juttermann R; Soloway PD. 2000. TIMP-2 is required for efficient activation of proMMP-2 in vivo J Biol Chem 275(34):26411-5. [PubMed: 10827175]  [MGI Ref ID J:64001]

Additional References

Timp2tm1Pds related

Aoki T; Kataoka H; Moriwaki T; Nozaki K; Hashimoto N. 2007. Role of TIMP-1 and TIMP-2 in the progression of cerebral aneurysms. Stroke 38(8):2337-45. [PubMed: 17569872]  [MGI Ref ID J:148151]

Basu R; Lee J; Morton JS; Takawale A; Fan D; Kandalam V; Wang X; Davidge ST; Kassiri Z. 2013. TIMP3 is the primary TIMP to regulate agonist-induced vascular remodelling and hypertension. Cardiovasc Res 98(3):360-71. [PubMed: 23524300]  [MGI Ref ID J:211441]

English JL; Kassiri Z; Koskivirta I; Atkinson SJ; Di Grappa M; Soloway PD; Nagase H; Vuorio E; Murphy G; Khokha R. 2006. Individual Timp deficiencies differentially impact pro-MMP-2 activation. J Biol Chem 281(15):10337-46. [PubMed: 16469749]  [MGI Ref ID J:112210]

Guan Y; Ackert-Bicknell CL; Kell B; Troyanskaya OG; Hibbs MA. 2010. Functional genomics complements quantitative genetics in identifying disease-gene associations. PLoS Comput Biol 6(11):e1000991. [PubMed: 21085640]  [MGI Ref ID J:168495]

Jaworski DM; Beem-Miller M; Lluri G; Barrantes-Reynolds R. 2007. Potential regulatory relationship between the nested gene DDC8 and its host gene tissue inhibitor of metalloproteinase-2. Physiol Genomics 28(2):168-78. [PubMed: 16985004]  [MGI Ref ID J:128681]

Jaworski DM; Boone J; Caterina J; Soloway P; Falls WA. 2005. Prepulse inhibition and fear-potentiated startle are altered in tissue inhibitor of metalloproteinase-2 (TIMP-2) knockout mice. Brain Res 1051(1-2):81-9. [PubMed: 15979591]  [MGI Ref ID J:99752]

Jaworski DM; Sideleva O; Stradecki HM; Langlois GD; Habibovic A; Satish B; Tharp WG; Lausier J; Larock K; Jetton TL; Peshavaria M; Pratley RE. 2011. Sexually dimorphic diet-induced insulin resistance in obese tissue inhibitor of metalloproteinase-2 (TIMP-2)-deficient mice. Endocrinology 152(4):1300-13. [PubMed: 21285317]  [MGI Ref ID J:173867]

Jaworski DM; Soloway P; Caterina J; Falls WA. 2006. Tissue inhibitor of metalloproteinase-2(TIMP-2)-deficient mice display motor deficits. J Neurobiol 66(1):82-94. [PubMed: 16216006]  [MGI Ref ID J:131430]

Kandalam V; Basu R; Abraham T; Wang X; Soloway PD; Jaworski DM; Oudit GY; Kassiri Z. 2010. TIMP2 deficiency accelerates adverse post-myocardial infarction remodeling because of enhanced MT1-MMP activity despite lack of MMP2 activation. Circ Res 106(4):796-808. [PubMed: 20056917]  [MGI Ref ID J:170876]

Kandalam V; Basu R; Moore L; Fan D; Wang X; Jaworski DM; Oudit GY; Kassiri Z. 2011. Lack of tissue inhibitor of metalloproteinases 2 leads to exacerbated left ventricular dysfunction and adverse extracellular matrix remodeling in response to biomechanical stress. Circulation 124(19):2094-105. [PubMed: 21986284]  [MGI Ref ID J:189458]

Kim KH; Burkhart K; Chen P; Frevert CW; Randolph-Habecker J; Hackman RC; Soloway PD; Madtes DK. 2005. Tissue inhibitor of metalloproteinase-1 deficiency amplifies acute lung injury in bleomycin-exposed mice. Am J Respir Cell Mol Biol 33(3):271-9. [PubMed: 15947421]  [MGI Ref ID J:112941]

Lluri G; Langlois GD; Soloway PD; Jaworski DM. 2008. Tissue inhibitor of metalloproteinase-2 (TIMP-2) regulates myogenesis and beta1 integrin expression in vitro. Exp Cell Res 314(1):11-24. [PubMed: 17678891]  [MGI Ref ID J:145122]

Ma S; Kwon HJ; Johng H; Zang K; Huang Z. 2013. Radial glial neural progenitors regulate nascent brain vascular network stabilization via inhibition of Wnt signaling. PLoS Biol 11(1):e1001469. [PubMed: 23349620]  [MGI Ref ID J:194480]

Mi M; Shi S; Li T; Holz J; Lee YJ; Sheu TJ; Liao Q; Xiao T. 2012. TIMP2 deficient mice develop accelerated osteoarthritis via promotion of angiogenesis upon destabilization of the medial meniscus. Biochem Biophys Res Commun 423(2):366-72. [PubMed: 22664108]  [MGI Ref ID J:185352]

Perez-Martinez L; Jaworski DM. 2005. Tissue inhibitor of metalloproteinase-2 promotes neuronal differentiation by acting as an anti-mitogenic signal. J Neurosci 25(20):4917-29. [PubMed: 15901773]  [MGI Ref ID J:98527]

Sabeh F; Li XY; Saunders TL; Rowe RG; Weiss SJ. 2009. Secreted versus membrane-anchored collagenases: relative roles in fibroblast-dependent collagenolysis and invasion. J Biol Chem 284(34):23001-11. [PubMed: 19542530]  [MGI Ref ID J:153449]

Vaillant B; Chiaramonte MG; Cheever AW; Soloway PD; Wynn TA. 2001. Regulation of hepatic fibrosis and extracellular matrix genes by the th response: new insight into the role of tissue inhibitors of matrix metalloproteinases. J Immunol 167(12):7017-26. [PubMed: 11739522]  [MGI Ref ID J:73095]

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 & HusbandryWhen maintaining a live colony, these mice can be bred as homozygotes.

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls


Pricing for USA, Canada and Mexico shipping destinations View International Pricing

Cryopreserved

Cryopreserved Mice - Ready for Recovery

Price (US dollars $)
Cryorecovery* $2140.00
Animals Provided

At least two mice that carry the mutation (if it is a mutant strain) will be provided. Their genotypes may not reflect those discussed in the strain description. Please inquire for possible genotypes and see additional details below.

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Supply Notes

  • Cryorecovery - Standard.
    Progeny testing is not required.

    The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided, their gender and genotype will vary. We will fulfill your order by providing at least two pair of mice, at least one animal of each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 10 and 14 weeks from the date of your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will ship within 25 weeks. IMPORTANT NOTE: The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

    Cryorecovery to establish a Dedicated Supply for greater quantities of mice. Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 (from U.S.A., Canada or Puerto Rico only) or 1-207-288-5845 (from any location).

Pricing for International shipping destinations View USA Canada and Mexico Pricing

Cryopreserved

Cryopreserved Mice - Ready for Recovery

Price (US dollars $)
Cryorecovery* $2782.00
Animals Provided

At least two mice that carry the mutation (if it is a mutant strain) will be provided. Their genotypes may not reflect those discussed in the strain description. Please inquire for possible genotypes and see additional details below.

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Supply Notes

  • Cryorecovery - Standard.
    Progeny testing is not required.

    The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided, their gender and genotype will vary. We will fulfill your order by providing at least two pair of mice, at least one animal of each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 10 and 14 weeks from the date of your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will ship within 25 weeks. IMPORTANT NOTE: The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

    Cryorecovery to establish a Dedicated Supply for greater quantities of mice. Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 (from U.S.A., Canada or Puerto Rico only) or 1-207-288-5845 (from any location).

View USA Canada and Mexico Pricing View International Pricing

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Control Information

  Control
   000664 C57BL/6J
 
  Considerations for Choosing Controls
  Control Pricing Information for Genetically Engineered Mutant Strains.
 

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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.
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