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| Mice harboring both the Ins2-rtTA (or RIP7-rtTA) transgene and the tet-DTA (or tetO-DTA) transgene have doxycycline-inducible expression of DTA in pancreatic beta cells; i.e. addition of doxycycline results in ablation of pancreatic beta cells. | |||||||||||||||||||
- Description
- Disease & phenotype
- Genes & alleles
- Genotyping
- Health & care
- References
- Pricing & purchasing
- Terms of use
Description
Strain Information
Type Mutant Stock; Transgenic; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Mating System See Colony Maintenance under the Health & husbandry tab (Female x Male) 16-NOV-09 Species laboratory mouse Generation F10 (16-SEP-12)
Generation DefinitionsDonating Investigator IMR Colony, The Jackson Laboratory Description
This strain was generated by breeding Stock No. 008168 and Stock No. 008250 together at The Jackson Laboratory. The resulting double transgenic colony was established as Stock No. 008755.The Ins2-rtTA (or RIP7-rtTA) transgene expresses the reverse tetracycline-controlled transactivator (rtTA) protein under the control of the rat insulin 2 (Ins2) promoter. The tet-DTA (or tetO-DTA) (transgene expresses diphtheria toxin A (DTA) under the control of a tetracycline operator (tetO; also called tetracycline-responsive element (TRE) or tet-operator) and a cytomegalovirus minimal promoter. Mice harboring both of these transgenes has doxycycline-inducible expression of DTA in pancreatic beta cells; i.e. addition of the tetracycline analogue doxycycline (dox) results in ablation of pancreatic beta cells.
Development
This strain was generated by breeding Stock No. 008168 and Stock No. 008250 together at The Jackson Laboratory. The resulting double transgenic colony was established (as Stock No. 008755). This strain was subsequently maintained by breeding mice carrying for both the RIP7-rtTA transgene and tet-DTA transgene together. The genetic background is a mix of C57BL/6, CBA, and outbred ICR.
Control Information
| Control | ||
|---|---|---|
| None Available | ||
| Considerations for Choosing Controls | ||
Related Strains
Strains carrying Tg(Ins2-rtTA)2Efr allele
008250 STOCK Tg(Ins2-rtTA)2Efr/J View Strains carrying Tg(Ins2-rtTA)2Efr (1 strain)
008468 B6.Cg-Tg(tetO-DTA)1Gfi/J 008168 STOCK Tg(tetO-DTA)1Gfi/J
008617 B6(A)-Tg(OPN1LW-DT)1Mame/J 007942 B6.Cg-Isl2tm1Arbr/J 017949 B6.FVB-Tg(CD207-Dta)312Dhka/J 006576 B6.FVB-Tg(GNAT2-Dta)98Wwk/J 002384 FVB/N-Tg(UcpDta)1Kz/J
Additional Web Information
Tet Expression Systems
Phenotype
Phenotype Information
assigned by genotype
The following phenotype information may relate to a genetic background differing from this JAX® Mice strain.
Tg(Ins2-rtTA)2Efr/0 Tg(tetO-DTA)1Gfi/0
involves: C57BL/6 * CBA
- endocrine/exocrine gland phenotype
- *normal* endocrine/exocrine gland phenotype
- average size of regenerating beta cells is same as original cells (MGI Ref ID J:127412)
- abnormal pancreas morphology
- pancreatic insulin content is reduced by ~85%; after doxycycline withdrawal, pancreatic insulin level return to near control levels (MGI Ref ID J:127412)
- abnormal pancreatic beta cell morphology
- frequency of insulin-positive, glucagons-positive beta cells increases from 1:5500 in controls to 1:1000 beta cells in diabetic transgenic mice (MGI Ref ID J:127412)
- permitting doxycycline-treated mice to recover in presence of immunosupressants Sirolimus and Tacrolimus (SirTac) significantly reduces beta cell proliferation and beta cell mass does not increase as it does in absence of immunosupressants; blood glucose levels in treated mice fail to normalize as they do in controls treated with SirTac (MGI Ref ID J:127412)
- decreased pancreatic beta cell number
- 70-80% of beta cells are lost in doxycycline-treated 5-week old double-transgenic mice relative to controls (MGI Ref ID J:127412)
- similar results are obtained when beta cells are ablated between birth and five weeks of age; beta cell mass normalizes within ~15 weeks of doxycycline withdrawal (MGI Ref ID J:127412)
- increased pancreatic beta cell number
- rate of beta cell apoptosis in recovering mice is not different from controls, but beta cell proliferation is increased 2-3-fold within 48 hours of onset of beta cell ablation; this increased proliferation rate is maintained for several weeks (MGI Ref ID J:127412)
- disorganized pancreatic islets
- treatment of four-week old mice with doxycycline for 1 week results in severely disrupted islet architecture with non-beta cells at the core of shriveled islets rather than beta cells (MGI Ref ID J:127412)
- after withdrawal of doxycycline, normalization of islet architecture occurs in ~90% of islets (MGI Ref ID J:127412)
- homeostasis/metabolism phenotype
- *normal* homeostasis/metabolism phenotype
- peripheral insulin sensitivity after beta cell regeneration is similar to controls after doxycycline withdrawal, beta cell mass in transgenic mice increases to levels comparable to wild-type (MGI Ref ID J:127412)
- improved glucose tolerance
- after more than 8 months without doxycycline, glucose tolerance starts to recover (MGI Ref ID J:127412)
- similar results are obtained when beta cells are ablated between birth and five weeks of age; beta cell mass normalizes within ~15 weeks of doxycycline withdrawal (MGI Ref ID J:127412)
- mice that showed severe, chronic or adult-onset (starting at 4 months) hyperglycemia spontaneously normalized blood glucose levels and beta-cell mass after doxycycline withdrawal (MGI Ref ID J:127412)
- increased circulating glucose level
- blood glucose levels of treated mice are elevated to 300-600 mg/dl making the mice overtly diabetic; after withdrawal of doxycycline, blood glucose levels return to normal level (MGI Ref ID J:127412)
- mice that showed severe, chronic or adult-onset (starting at 4 months) hyperglycemia spontaneously normalized blood glucose levels and beta-cell mass after doxycycline withdrawal (MGI Ref ID J:127412)
- hyperglycemia
- blood glucose levels are elevated to 300-600 mg/dl; after doxycycline withdrawal, remission of hyperglycemia occurs such that fed and fasting glucose levels normalize (MGI Ref ID J:127412)
- mice that showed severe, chronic or adult-onset (starting at 4 months) hyperglycemia spontaneously normalized blood glucose levels and beta-cell mass after doxycycline withdrawal (MGI Ref ID J:127412)
- cellular phenotype
- increased apoptosis
- widespread pancreatic beta cell apoptosis is seen within 48 hours of doxycycline treatment of double-transgenic mice, but no apoptosis is observed in single transgenic littermates (MGI Ref ID J:127412)
This mouse can be used to support research in many areas including:
Diabetes and Obesity Research
Type 1 Diabetes (IDDM)
Endocrine Deficiency Research
Pancreas Defects
Immunology, Inflammation and Autoimmunity Research
Autoimmunity
Type 1 Diabetes
Metabolism Research
Enzyme Deficiency
exocrine pancreatic insufficiency
Neurobiology Research
Tet Expression System
tTA/rtTA Expressing Strains
tTA/rtTA Responsive Strains
Research Tools
Cancer Research
Tetop Tet System
Cardiovascular Research
Tetop Tet System
Diabetes and Obesity Research
Genetics Research
Mutagenesis and Transgenesis
Mutagenesis and Transgenesis: Tetop Tet System
Tissue/Cell Markers
Tissue/Cell Markers: pancreatic beta cells
Neurobiology Research
Tetop Tet System
Tet Expression Systems
tTA/rtTA Expressing Strains
tTA/rtTA Responsive Strains
Genes & Alleles
Gene & Allele Information provided by MGI
| Allele Symbol | Tg(Ins2-rtTA)2Efr | ||
|---|---|---|---|
| Allele Name | transgene insertion 2, Shimon Efrat | ||
| Allele Type | Transgenic (random, expressed) | ||
| Common Name(s) | Ins-rtTA; RIP7-rtTA; RiprtTA; | ||
| Strain of Origin | (C57BL/6 x CBA)F2 | ||
| Site of Expression | pancreatic beta cells | ||
| Expressed Gene | rtTA, reverse tetracycline-controlled transactivator, E. coli | ||
| The tetracycline repressor gene (Tetr), arose from chemically mutated Escherichia coli genome which was screened for tetracycline dependence (Gossen and Bujard, 1992). One mutant with a four amino acid residue change (rTetR) exhibited dependence on tetracycline for induction of the targeted gene and was used in the rtTA construct (Gossen et al, 1995). rTetr was fused at the C-terminus with the viral co-activator, virion protein 16 of the herpes simplex virus (VP-16). | |||
| Promoter | Ins2, insulin 2, rat | ||
| Molecular Note | A transgenic construct containing 9.5kb 5' regulatory sequence and first intron of the rat insulin 2 gene (RIP7) controlling the reverse tetracycline transactivator (rtTA), as well as the polyadenylation site sequence of the RIP7 gene was injected into fertilized (C57BL/6 X CBA)F2 mouse eggs. Founder line 2 with 10 copies of the transgene was established. When mice are crossed to transgenic mice carrying reporter genes, transgene expression is detected only in pancreatic islet beta cells. [MGI Ref ID J:130049] | ||
| Allele Symbol | Tg(tetO-DTA)1Gfi | ||
| Allele Name | transgene insertion 1, Glenn I Fishman | ||
| Allele Type | Transgenic (random, expressed) | ||
| Common Name(s) | tet-DTA; tetODTA/+; | ||
| Strain of Origin | (C57BL/6 x CBA)F2 | ||
| Site of Expression | pancreatic beta cells | ||
| Expressed Gene | Dta, Diphtheria toxin A chain, | ||
| Promoter | tetO, tet operator, | ||
| Molecular Note | A transgenic construct was created, containing diphtheria toxin A sequence (DTA) under the control of heptamerized tetracycline operator, tetO sequences fused to a cytomegalovirus minimal promoter. [MGI Ref ID J:128617] | ||
Genotyping
Genotyping Information
Genotyping Protocols
Tg(tTA), QPCR
Tg(tetO-DTA)1Gfi, QPCR
Helpful Links
Genotyping resources and troubleshooting
References
References provided by MGI
Selected Reference(s)
Lee P; Morley G; Huang Q; Fischer A; Seiler S; Horner JW; Factor S; Vaidya D; Jalife J; Fishman GI. 1998. Conditional lineage ablation to model human diseases. Proc Natl Acad Sci U S A 95(19):11371-6. [PubMed: 9736743] [MGI Ref ID J:128617]
Milo-Landesman D; Surana M; Berkovich I; Compagni A; Christofori G; Fleischer N; Efrat S. 2001. Correction of hyperglycemia in diabetic mice transplanted with reversibly immortalized pancreatic beta cells controlled by the tet-on regulatory system. Cell Transplant 10(7):645-50. [PubMed: 11714200] [MGI Ref ID J:130049]
Additional References
Tg(Ins2-rtTA)2Efr relatedTg(tetO-DTA)1Gfi relatedBalcazar N; Sathyamurthy A; Elghazi L; Gould A; Weiss A; Shiojima I; Walsh K; Bernal-Mizrachi E. 2009. mTORC1 activation regulates beta-cell mass and proliferation by modulation of cyclin D2 synthesis and stability. J Biol Chem 284(12):7832-42. [PubMed: 19144649] [MGI Ref ID J:148614]
Berkovich I; Efrat S. 2001. Inducible and Reversible beta-Cell Autoimmunity and Hyperplasia in Transgenic Mice Expressing a Conditional Oncogene. Diabetes 50(10):2260-7. [PubMed: 11574407] [MGI Ref ID J:71705]
Cai Q; Brissova M; Reinert RB; Pan FC; Brahmachary P; Jeansson M; Shostak A; Radhika A; Poffenberger G; Quaggin SE; Jerome WG; Dumont DJ; Powers AC. 2012. Enhanced expression of VEGF-A in beta cells increases endothelial cell number but impairs islet morphogenesis and beta cell proliferation. Dev Biol 367(1):40-54. [PubMed: 22546694] [MGI Ref ID J:185806]
Eldor R; Yeffet A; Baum K; Doviner V; Amar D; Ben-Neriah Y; Christofori G; Peled A; Carel JC; Boitard C; Klein T; Serup P; Eizirik DL; Melloul D. 2006. Conditional and specific NF-kappaB blockade protects pancreatic beta cells from diabetogenic agents. Proc Natl Acad Sci U S A 103(13):5072-7. [PubMed: 16551748] [MGI Ref ID J:107655]
Gupta S; McGrath B; Cavener DR. 2009. PERK regulates the proliferation and development of insulin-secreting beta-cell tumors in the endocrine pancreas of mice. PLoS One 4(11):e8008. [PubMed: 19956728] [MGI Ref ID J:155377]
Jaggi F; Cabrita MA; Perl AK; Christofori G. 2008. Modulation of endocrine pancreas development but not beta-cell carcinogenesis by Sprouty4. Mol Cancer Res 6(3):468-82. [PubMed: 18337453] [MGI Ref ID J:138091]
Nir T; Melton DA; Dor Y. 2007. Recovery from diabetes in mice by beta cell regeneration. J Clin Invest 117(9):2553-61. [PubMed: 17786244] [MGI Ref ID J:127412]
Porat S; Weinberg-Corem N; Tornovsky-Babaey S; Schyr-Ben-Haroush R; Hija A; Stolovich-Rain M; Dadon D; Granot Z; Ben-Hur V; White P; Girard CA; Karni R; Kaestner KH; Ashcroft FM; Magnuson MA; Saada A; Grimsby J; Glaser B; Dor Y. 2011. Control of pancreatic beta cell regeneration by glucose metabolism. Cell Metab 13(4):440-9. [PubMed: 21459328] [MGI Ref ID J:172243]
Pullen TJ; Sylow L; Sun G; Halestrap AP; Richter EA; Rutter GA. 2012. Overexpression of monocarboxylate transporter-1 (SLC16A1) in mouse pancreatic beta-cells leads to relative hyperinsulinism during exercise. Diabetes 61(7):1719-25. [PubMed: 22522610] [MGI Ref ID J:192583]
Sodir NM; Swigart LB; Karnezis AN; Hanahan D; Evan GI; Soucek L. 2011. Endogenous Myc maintains the tumor microenvironment. Genes Dev 25(9):907-16. [PubMed: 21478273] [MGI Ref ID J:171447]
Nir T; Melton DA; Dor Y. 2007. Recovery from diabetes in mice by beta cell regeneration. J Clin Invest 117(9):2553-61. [PubMed: 17786244] [MGI Ref ID J:127412]
Porat S; Weinberg-Corem N; Tornovsky-Babaey S; Schyr-Ben-Haroush R; Hija A; Stolovich-Rain M; Dadon D; Granot Z; Ben-Hur V; White P; Girard CA; Karni R; Kaestner KH; Ashcroft FM; Magnuson MA; Saada A; Grimsby J; Glaser B; Dor Y. 2011. Control of pancreatic beta cell regeneration by glucose metabolism. Cell Metab 13(4):440-9. [PubMed: 21459328] [MGI Ref ID J:172243]
Stanger BZ; Tanaka AJ; Melton DA. 2007. Organ size is limited by the number of embryonic progenitor cells in the pancreas but not the liver. Nature 445(7130):886-91. [PubMed: 17259975] [MGI Ref ID J:118596]
Health & husbandry
Health & Colony Maintenance Information
Animal Health Reports
Room Number AX11
Colony Maintenance
Breeding & Husbandry This strain was generated by breeding Stock No. 008168 and Stock No. 008250 together at The Jackson Laboratory. The resulting double transgenic colony was established (as Stock No. 008755). This strain was subsequently maintained by breeding mice carrying both the RIP7-rtTA transgene and tet-DTA transgene together. The genetic background is a mix of C57BL/6, CBA, and outbred ICR. Mating System See Colony Maintenance under the Health & husbandry tab (Female x Male) 16-NOV-09 Diet Information LabDiet® 5K52/5K67
Pricing and Purchasing
Pricing, Supply Level & Notes, Controls
| Pricing for USA, Canada and Mexico shipping destinations |
|
Live Mice
Price per mouse (US dollars $) Gender Genotypes Provided Individual Mouse $232.00 Female or Male Homozygous for Tg(Ins2-rtTA)2Efr, Homozygous for Tg(teto-DTA)1Gfi
Price per Pair (US dollars $) Pair Genotype $464.00 Homozygous for Tg(Ins2-rtTA)2Efr, Homozygous for Tg(teto-DTA)1Gfi x Homozygous for Tg(Ins2-rtTA)2Efr, Homozygous for Tg(teto-DTA)1Gfi Standard Supply
Repository-Live. Repository-Live represents an exclusive set of over 1500 unique mouse models maintained at The Jackson Laboratory to support a vast array of research areas. The breeding colonies for Repository Strains provide mice for both large and small orders and fluctuate in size depending on current demand for each strain. Repository-live orders are treated as custom orders. Within 2 business days, we respond to each availability inquiry or order with various delivery options. Repository Strains typically are delivered at 4 to 8 weeks of age and will not exceed 12 weeks of age on the day of shipping.
| Pricing for International shipping destinations |
|
Live Mice
Price per mouse (US dollars $) Gender Genotypes Provided Individual Mouse $301.60 Female or Male Homozygous for Tg(Ins2-rtTA)2Efr, Homozygous for Tg(teto-DTA)1Gfi
Price per Pair (US dollars $) Pair Genotype $603.20 Homozygous for Tg(Ins2-rtTA)2Efr, Homozygous for Tg(teto-DTA)1Gfi x Homozygous for Tg(Ins2-rtTA)2Efr, Homozygous for Tg(teto-DTA)1Gfi Standard Supply
Repository-Live. Repository-Live represents an exclusive set of over 1500 unique mouse models maintained at The Jackson Laboratory to support a vast array of research areas. The breeding colonies for Repository Strains provide mice for both large and small orders and fluctuate in size depending on current demand for each strain. Repository-live orders are treated as custom orders. Within 2 business days, we respond to each availability inquiry or order with various delivery options. Repository Strains typically are delivered at 4 to 8 weeks of age and will not exceed 12 weeks of age on the day of shipping.
|
|
|
Standard Supply
Repository-Live. Repository-Live represents an exclusive set of over 1500 unique mouse models maintained at The Jackson Laboratory to support a vast array of research areas. The breeding colonies for Repository Strains provide mice for both large and small orders and fluctuate in size depending on current demand for each strain. Repository-live orders are treated as custom orders. Within 2 business days, we respond to each availability inquiry or order with various delivery options. Repository Strains typically are delivered at 4 to 8 weeks of age and will not exceed 12 weeks of age on the day of shipping.
General Supply Notes
- Genomic DNA is available for this strain from the Mouse DNA Resource.
Control Information
| Control | ||
|---|---|---|
| None Available | ||
| 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.Ordering Information
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