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 Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Species laboratory mouse   Donating Investigator David J. Kwiatkowski,   Brigham and Women's Hospital

Description
Mice that are heterozygous for the targeted mutation are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. Homozygous null mice have an embryonic lethal phenotype, failing to develop past embryonic days 9.5 to 12.5 due to hepatic hypoplasia. Cultured neuroepithelial progenitor cells isolated from embryonic day 10.5 embryos display abnormal growth and differentiation. All heterozygotes develop multiple bilateral renal cystadenomas by 12-15 months of age. By 15 months, about half develop liver hemangiomas (more common in females than in males). Less than 10% develop extremity angiosarcomas or renal carcinoma. Little or no gene product (protein) is detected by Western blot in renal cystadenomas. PCR analysis reveals loss of the wildtype allele in about 30% of lesions. Phenotype variability is dependent on genetic background. This mutant mouse strain may be useful in studies of tuberous sclerosis (TSC).

Development
A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was used to disrupt exon 2 of the targeted gene. The construct was electroporated into 129S4/SvJae-derived J1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts.

Control Information

	Control
	Wild-type from the colony
	101045 B6129SF2/J	(approximate)
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Tsc2

014564

C57BL/6-Tg(CMV-Tsc2*)1Arbi/KlanJ

View Strains carrying other alleles of Tsc2     (1 strain)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Tuberous Sclerosis 2; TSC2

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Lymphangioleiomyomatosis; LAM   (TSC2)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Tsc2^tm1Djk/Tsc2⁺

        either: (involves: 129S4/SvJae * BALB/cJ) or (involves: 129S4/SvJae * Black Swiss) or (involves: 129S4/SvJae * C57BL/6J)

• tumorigenesis
• increased tumor incidence
  • reported at 15 months of age   (MGI Ref ID J:57631)
  • note that the tumor expression pattern is influenced by genetic background; authors note fewer large renal cystadenomas in outbred Black Swiss background and more angiosarcomas in 129S4/SvJae chimeric mice note that the tumor expression pattern is influenced by genetic background; authors note fewer large renal cystadenomas in outbred Black Swiss background and more angiosarcomas in 129S4/SvJae chimeric mice   (MGI Ref ID J:57631)
• • extremity angiosarcoma
    • less than 10% incidence   (MGI Ref ID J:57631)
  • hepatic hemangioma
    • 50% incidence; causes fatal bleeding in 10% of these cases   (MGI Ref ID J:57631)
  • increased lung adenoma incidence
    • 32% incidence   (MGI Ref ID J:57631)
  • increased renal carcinoma incidence
    • less than 10% incidence   (MGI Ref ID J:57631)
  • increased renal cystadenoma incidence
    • 100% incidence   (MGI Ref ID J:57631)

Tsc2^tm1Djk/Tsc2⁺

        involves: 129S4/SvJae * C57BL/6NCrl

• behavior/neurological phenotype
• *normal* behavior/neurological phenotype
  • mice exhibit normal motor skills, exploratory behavior, anxiety and social approach behavior   (MGI Ref ID J:138621)
• • abnormal contextual conditioning behavior
    • following contextual conditioning, mice exhibit reduced freezing compared to wild-type mice   (MGI Ref ID J:138621)
    • however, treatment with rapamycin re-establishes normal contextual conditioning   (MGI Ref ID J:138621)
  • abnormal spatial learning
    • in a hippocampus-dependent version of the Morris water maze test, spatial learning is impaired compared to in wild-type mice   (MGI Ref ID J:138621)
    • however, spatial learning in a hippocampus-independent water maze is normal and treatment with rapamycin re-establishes normal spatial learning   (MGI Ref ID J:138621)
    • mice exhibit more across-phase errors compared to in wild-type mice in a hippocampus-dependent win-shift version of the eight-arm radial maze   (MGI Ref ID J:138621)
• nervous system phenotype
• *normal* nervous system phenotype
  • mice exhibit normal basal synaptic transmission, paired-pulse facilitation and early-phase long term potentiation   (MGI Ref ID J:138621)
• • enhanced long term potentiation
    • mice exhibit lowered late-phase threshold for long term potentiation compared to in wild-type mice   (MGI Ref ID J:138621)
    • however, treatment with rapamycin re-establishes normal late-phase long term potentiation   (MGI Ref ID J:138621)

Tsc2^tm1Djk/Tsc2^tm1Djk

        either: (involves: 129S4/SvJae * BALB/cJ) or (involves: 129S4/SvJae * Black Swiss) or (involves: 129S4/SvJae * C57BL/6J)

• mortality/aging
• complete embryonic lethality during organogenesis
  • age of onset E9.5   (MGI Ref ID J:57631)
• liver/biliary system phenotype
• liver hypoplasia   (MGI Ref ID J:57631)

View Research Applications

Research Applications

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

Developmental Biology Research
Embryonic Lethality (Homozygous)

Tsc2^tm1Djk related

Cancer Research
Increased Tumor Incidence
      Adenomas
      Other Tissues/Organs
      Other Tissues/Organs: lung

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Tsc2tm1Djk
Allele Name		targeted mutation 1, David J Kwiatkowski
Allele Type		Targeted (knock-out)
Common Name(s)		Tsc2-; Tsc-;
Mutation Made By		David Kwiatkowski,   Brigham and Women's Hospital
Strain of Origin		129S4/SvJae
ES Cell Line Name		J1
ES Cell Line Strain		129S4/SvJae
Gene Symbol and Name		Tsc2, tuberous sclerosis 2
Chromosome		17
Gene Common Name(s)		LAM; Nafld; Rc; TSC4; tuberin;
Molecular Note		A neomycin cassette was inserted into the second coding exon of the gene. [MGI Ref ID J:57631]

Genotyping

Genotyping Information

Genotyping Protocols

Tsc2^tm1Djkalternate2,

SEPARATED MELT

Tsc2^tm1Djkalternate2, Separated PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Onda H; Lueck A; Marks PW; Warren HB; Kwiatkowski DJ. 1999. Tsc2(+/-) mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background. J Clin Invest 104(6):687-95. [PubMed: 10491404]  [MGI Ref ID J:57631]

Additional References

Uhlmann EJ; Apicelli AJ; Baldwin RL; Burke SP; Bajenaru ML; Onda H; Kwiatkowski D; Gutmann DH. 2002. Heterozygosity for the tuberous sclerosis complex (TSC) gene products results in increased astrocyte numbers and decreased p27-Kip1 expression in TSC2+/- cells. Oncogene 21(25):4050-9. [PubMed: 12037687]  [MGI Ref ID J:77179]

Tsc2^tm1Djk related

Auerbach BD; Osterweil EK; Bear MF. 2011. Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 480(7375):63-8. [PubMed: 22113615]  [MGI Ref ID J:178293]

Bae SH; Sung SH; Oh SY; Lim JM; Lee SK; Park YN; Lee HE; Kang D; Rhee SG. 2013. Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation of Keap1 and prevent oxidative liver damage. Cell Metab 17(1):73-84. [PubMed: 23274085]  [MGI Ref ID J:195093]

Blando J; Portis M; Benavides F; Alexander A; Mills G; Dave B; Conti CJ; Kim J; Walker CL. 2009. PTEN deficiency is fully penetrant for prostate adenocarcinoma in C57BL/6 mice via mTOR-dependent growth. Am J Pathol 174(5):1869-79. [PubMed: 19395652]  [MGI Ref ID J:148013]

Bonnet CS; Aldred M; von Ruhland C; Harris R; Sandford R; Cheadle JP. 2009. Defects in cell polarity underlie TSC and ADPKD-associated cystogenesis. Hum Mol Genet 18(12):2166-76. [PubMed: 19321600]  [MGI Ref ID J:148543]

Brown AB; Mahmood U; Cortes ML; Tang Y; Dai G; Stemmer-Rachamimov A; Prabhakar S; Leishear K; Onda H; Kwiatkowski D; Weissleder R; Breakefield X. 2005. Magnetic resonance imaging and characterization of spontaneous lesions in a transgenic mouse model of tuberous sclerosis as a model for endothelial cell-based transgene delivery. Hum Gene Ther 16(12):1367-76. [PubMed: 16390268]  [MGI Ref ID J:107438]

Cao J; Gong L; Guo DC; Mietzsch U; Kuang SQ; Kwartler CS; Safi H; Estrera A; Gambello MJ; Milewicz DM. 2010. Thoracic aortic disease in tuberous sclerosis complex: molecular pathogenesis and potential therapies in Tsc2+/- mice. Hum Mol Genet 19(10):1908-20. [PubMed: 20159776]  [MGI Ref ID J:159339]

Dibble CC; Elis W; Menon S; Qin W; Klekota J; Asara JM; Finan PM; Kwiatkowski DJ; Murphy LO; Manning BD. 2012. TBC1D7 Is a Third Subunit of the TSC1-TSC2 Complex Upstream of mTORC1. Mol Cell 47(4):535-46. [PubMed: 22795129]  [MGI Ref ID J:187614]

Ehninger D; Han S; Shilyansky C; Zhou Y; Li W; Kwiatkowski DJ; Ramesh V; Silva AJ. 2008. Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis. Nat Med 14(8):843-8. [PubMed: 18568033]  [MGI Ref ID J:138621]

Hartman TR; Liu D; Zilfou JT; Robb V; Morrison T; Watnick T; Henske EP. 2009. The tuberous sclerosis proteins regulate formation of the primary cilium via a rapamycin-insensitive and polycystin 1-independent pathway. Hum Mol Genet 18(1):151-63. [PubMed: 18845692]  [MGI Ref ID J:143404]

Huang J; Wu S; Wu CL; Manning BD. 2009. Signaling events downstream of mammalian target of rapamycin complex 2 are attenuated in cells and tumors deficient for the tuberous sclerosis complex tumor suppressors. Cancer Res 69(15):6107-14. [PubMed: 19602587]  [MGI Ref ID J:150957]

Kwiatkowski DJ; Zhang H; Bandura JL; Heiberger KM; Glogauer M; el-Hashemite N; Onda H. 2002. A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. Hum Mol Genet 11(5):525-34. [PubMed: 11875047]  [MGI Ref ID J:75243]

Lee L; Sudentas P; Donohue B; Asrican K; Worku A; Walker V; Sun Y; Schmidt K; Albert MS; El-Hashemite N; Lader AS; Onda H; Zhang H; Kwiatkowski DJ; Dabora SL. 2005. Efficacy of a rapamycin analog (CCI-779) and IFN-gamma in tuberous sclerosis mouse models. Genes Chromosomes Cancer 42(3):213-27. [PubMed: 15578690]  [MGI Ref ID J:95229]

Ma L; Teruya-Feldstein J; Behrendt N; Chen Z; Noda T; Hino O; Cordon-Cardo C; Pandolfi PP. 2005. Genetic analysis of Pten and Tsc2 functional interactions in the mouse reveals asymmetrical haploinsufficiency in tumor suppression. Genes Dev 19(15):1779-86. [PubMed: 16027168]  [MGI Ref ID J:100094]

Mak BC; Kenerson HL; Aicher LD; Barnes EA; Yeung RS. 2005. Aberrant beta-catenin signaling in tuberous sclerosis. Am J Pathol 167(1):107-16. [PubMed: 15972957]  [MGI Ref ID J:99509]

Manning BD; Logsdon MN; Lipovsky AI; Abbott D; Kwiatkowski DJ; Cantley LC. 2005. Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2. Genes Dev 19(15):1773-8. [PubMed: 16027169]  [MGI Ref ID J:100095]

Nie D; Di Nardo A; Han JM; Baharanyi H; Kramvis I; Huynh T; Dabora S; Codeluppi S; Pandolfi PP; Pasquale EB; Sahin M. 2010. Tsc2-Rheb signaling regulates EphA-mediated axon guidance. Nat Neurosci 13(2):163-72. [PubMed: 20062052]  [MGI Ref ID J:156683]

Onda H; Crino PB; Zhang H; Murphey RD; Rastelli L; Gould Rothberg BE; Kwiatkowski DJ. 2002. Tsc2 Null Murine Neuroepithelial Cells Are a Model for Human Tuber Giant Cells, and Show Activation of an mTOR Pathway. Mol Cell Neurosci 21(4):561-74. [PubMed: 12504590]  [MGI Ref ID J:81245]

Parkhitko A; Myachina F; Morrison TA; Hindi KM; Auricchio N; Karbowniczek M; Wu JJ; Finkel T; Kwiatkowski DJ; Yu JJ; Henske EP. 2011. Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent. Proc Natl Acad Sci U S A 108(30):12455-60. [PubMed: 21746920]  [MGI Ref ID J:174534]

Pollizzi K; Malinowska-Kolodziej I; Doughty C; Betz C; Ma J; Goto J; Kwiatkowski DJ. 2009. A hypomorphic allele of Tsc2 highlights the role of TSC1/TSC2 in signaling to AKT and models mild human TSC2 alleles. Hum Mol Genet 18(13):2378-87. [PubMed: 19357198]  [MGI Ref ID J:149326]

Pollizzi K; Malinowska-Kolodziej I; Stumm M; Lane H; Kwiatkowski D. 2009. Equivalent benefit of mTORC1 blockade and combined PI3K-mTOR blockade in a mouse model of tuberous sclerosis. Mol Cancer 8:38. [PubMed: 19527517]  [MGI Ref ID J:157342]

Settembre C; Zoncu R; Medina DL; Vetrini F; Erdin S; Erdin S; Huynh T; Ferron M; Karsenty G; Vellard MC; Facchinetti V; Sabatini DM; Ballabio A. 2012. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J 31(5):1095-108. [PubMed: 22343943]  [MGI Ref ID J:182149]

Short JD; Houston KD; Dere R; Cai SL; Kim J; Johnson CL; Broaddus RR; Shen J; Miyamoto S; Tamanoi F; Kwiatkowski D; Mills GB; Walker CL. 2008. AMP-activated protein kinase signaling results in cytoplasmic sequestration of p27. Cancer Res 68(16):6496-506. [PubMed: 18701472]  [MGI Ref ID J:139145]

Uhlmann EJ; Apicelli AJ; Baldwin RL; Burke SP; Bajenaru ML; Onda H; Kwiatkowski D; Gutmann DH. 2002. Heterozygosity for the tuberous sclerosis complex (TSC) gene products results in increased astrocyte numbers and decreased p27-Kip1 expression in TSC2+/- cells. Oncogene 21(25):4050-9. [PubMed: 12037687]  [MGI Ref ID J:77179]

Wang CY; X738b X798e X9685; Stapleton DS; Schueler KL; Rabaglia ME; Oler AT; Keller MP; Kendziorski CM; Broman KW; Yandell BS; Schadt EE; Attie AD. 2012. Tsc2, a positional candidate gene underlying a quantitative trait locus for hepatic steatosis. J Lipid Res 53(8):1493-1501. [PubMed: 22628617]  [MGI Ref ID J:186560]

Yuan E; Tsai PT; Greene-Colozzi E; Sahin M; Kwiatkowski DJ; Malinowska IA. 2012. Graded loss of tuberin in an allelic series of brain models of TSC correlates with survival, and biochemical, histological and behavioral features. Hum Mol Genet 21(19):4286-300. [PubMed: 22752306]  [MGI Ref ID J:187405]

Zhang H; Cicchetti G; Onda H; Koon HB; Asrican K; Bajraszewski N; Vazquez F; Carpenter CL; Kwiatkowski DJ. 2003. Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR. J Clin Invest 112(8):1223-33. [PubMed: 14561707]  [MGI Ref ID J:162300]

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	The resulting chimeric animals were crossed to C57BL/6 mice. Heterozygotes were then intercrossed. Expected coat color is: Black
Diet Information	LabDiet® 5K52/5K67

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

General Supply Notes

• Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	Wild-type from the colony
	101045 B6129SF2/J	(approximate)
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

For Licensing and Use Restrictions view the link(s) below:
- Notice to customers in Canada.
- Use of MICE by companies or for-profit entities requires a license prior to shipping.

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.