Description

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. Mating System Homozygote x Homozygote         (Female x Male)   25-JUN-09 Species laboratory mouse Generation N13+N1F1 (07-OCT-09) Generation Definitions   Donating Investigator Paul 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

      assigned by genotype

Timp2^tm1Pds/Timp2^tm1Pds

        B6.129S4-Timp2^tm1Pds

• behavior/neurological phenotype
• abnormal cued conditioning behavior (MGI Ref ID J:99752)
  • 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)
  • 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
  • wild-type and heterozygous males acquire conditioned fear over the course of the test, but null and knockdown mice do not
  • females do not show any proportional increases in FPS
• nervous system phenotype
• decreased prepulse inhibition (MGI Ref ID J:99752)
  • Timp2-null mice have significantly reduced prepulse inhibition (PPI)

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 (MGI Ref ID J:112941)
  • 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
• immune system phenotype
• increased neutrophil cell number (MGI Ref ID J:112941)
  • 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
• homeostasis/metabolism phenotype
• abnormal enzyme/coenzyme activity (MGI Ref ID J:64001)
  • activation of proMMP-2 in vivo is dramatically altered with Timp2 deficiency

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

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; DNA segment, Chr 11, Brigham & Women's Genetics 1104 expressed; MGC105282; 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

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]

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; 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]

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]

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

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX11

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice can be bred as homozygotes.
Mating System	Homozygote x Homozygote         (Female x Male)   25-JUN-09
Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Live. A collection of over 1000 strains maintained as live colonies. Individual colonies are sized to meet current customer demand. Delivery for orders of 10 mice or less ranges on average from one to eight weeks; mice are generally shipped between four to six weeks of age with a maximum shipping age of approximately nine weeks. Colony sizes do not generally support stringent age specifications for large volumes of mice; however custom orders and/or larger quantities of mice may be possible. Estimated ship dates for all orders provided within two business days following order placement.

Supply Notes

Usually shipped between four and eight weeks of age. This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

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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.

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Terms of Use

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fax:	207-288-6655

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