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. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Species laboratory 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

Timp2^tm1Pds/Timp2^tm1Pds

        B6.129S4-Timp2^tm1Pds

• 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 may relate to a genetic background differing from this JAX^® Mice strain.

Timp2^tm1Pds/Timp2^tm1Pds

        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)

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 (knock-out)
Common Name(s)		TIMP-2KO; TIMP2KO; Timp2-;
Mutation Made By		Paul Soloway,   Cornell University
Strain of Origin		129S4/SvJae
ES Cell Line Name		J1
ES Cell Line Strain		129S4/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

Timp2^tm1Pds, 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

Timp2^tm1Pds 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]

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

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

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

Payment Terms and Conditions

Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

See Terms of Use tab for General Terms and Conditions

The Jackson Laboratory's Genotype Promise

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.

---

Ordering Information
JAX^® Mice
Surgical and Preconditioning Services
JAX^® Services
Customer Services and Support
Tel: 1-800-422-6423 or 1-207-288-5845
Fax: 1-207-288-6150
Technical Support Email Form

Terms of Use

Terms of Use

General Terms and Conditions

Contact information

General inquiries regarding Terms of Use

Contracts Administration

phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice, Products & Services Conditions of Use

"MICE" means mouse strains, their progeny derived by inbreeding or crossbreeding, unmodified derivatives from mouse strains or their progeny supplied by The Jackson Laboratory ("JACKSON"). "PRODUCTS" means biological materials supplied by JACKSON, and their derivatives. "RECIPIENT" means each recipient of MICE, PRODUCTS, or services provided by JACKSON including each institution, its employees and other researchers under its control. MICE or PRODUCTS shall not be: (i) used for any purpose other than the internal research, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services. Acceptance of MICE or PRODUCTS from JACKSON shall be deemed as agreement by RECIPIENT to these conditions, and departure from these conditions requires JACKSON's prior written authorization.

In case of dissatisfaction for a valid reason and claimed in writing by a purchaser within ninety (90) days of receipt of mice, products or services, JACKSON will, at its option, provide credit or replacement for the mice or product received or the services provided.

No Liability

In no event shall JACKSON, its trustees, directors, officers, employees, and affiliates be liable for any causes of action or damages, including any direct, indirect, special, or consequential damages, arising out of the provision of MICE, PRODUCTS or services, including economic damage or injury to property and lost profits, and including any damage arising from acts or negligence on the part of JACKSON, its agents or employees. Unless prohibited by law, in purchasing or receiving MICE, PRODUCTS or services from JACKSON, purchaser or recipient, or any party claiming by or through them, expressly releases and discharges JACKSON from all such causes of action or damages, and further agrees to defend and indemnify JACKSON from any costs or damages arising out of any third party claims.

MICE and PRODUCTS are to be used in a safe manner and in accordance with all applicable governmental rules and regulations.

The foregoing represents the General Terms and Conditions applicable to JACKSON’s MICE, PRODUCTS or services. In addition, special terms and conditions of sale of certain MICE, PRODUCTS or services may be set forth separately in JACKSON web pages, catalogs, price lists, contracts, and/or other documents, and these special terms and conditions shall also govern the sale of these MICE, PRODUCTS and services by JACKSON, and by its licensees and distributors.

Acceptance of delivery of MICE, PRODUCTS or services shall be deemed agreement to these terms and conditions. No purchase order or other document transmitted by purchaser or recipient that may modify the terms and conditions hereof, shall be in any way binding on JACKSON, and instead the terms and conditions set forth herein, including any special terms and conditions set forth separately, shall govern the sale of MICE, PRODUCTS or services by JACKSON.