Description

Strain Information

Former Names C;129S-Vhlhtm1Jae/J    (Changed: 11-SEP-08 ) Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Mating System Homozygote x Homozygote         (Female x Male) Species laboratory mouse Generation ?+F14 (31-DEC-07)   Donating Investigator Rudolf Jaenisch,   Massachusetts Institute of Technology

Description
This strain contains loxP sites flanking the Vhl promoter and exon 1 resulting in a conditional null allele. Mice that are homozygous for this allele are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. Cre-mediated recombination results in the deletion of the promoter and exon 1. Studies in which liver-specific inactivation of the Vhl gene was achieved by breeding this strain with albumin promoter driven-Cre mice (see Stock No. 003574 for example) resulted in hemizygous mice that exhibit cavernous hemangiomas of the liver, a rare component of the human von Hippel-Lindau (VHL) disease. This strain represents an effective tool for generating tissue specific-targeted mutants useful in studies examining VHL and tumor suppression in general.

Development
A vector containing Vhl exons 1-3 was used to construct the conditional allele. A positive-negative selection cassette, loxP-CMV-hyTK-loxP, was placed 2.6 Kb upstream of exon 1 and a loxP site positioned within intron 1. The targeting vector was electroporated into 129S4/SvJae-derived J1 embryonic stem cells which were subsequently transfected with a cytomegalovirus-driven Cre recombinase plasmid. ES cells in which Cre recombination resulted in exon 1 and the promoter being flanked by loxP sites (the 2-lox allele) were injected into BALB/c blastocysts.

Control Information

	Control
	None Available
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Vhl

003123

129S;ICR-Vhltm1Bjg/J

View Strains carrying other alleles of Vhl     (1 strain)

Additional Web Information

Cre-lox Systems

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

Von Hippel-Lindau Syndrome; VHL - Models with phenotypic similarity to human disease where etiologies involve orthologs.1

1 Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Vhl^tm1Jae/Vhl^tm1Jae

        involves: 129S4/SvJae * BALB/c

• normal phenotype
• no abnormal phenotype detected (MGI Ref ID J:67505)

The following phenotype relates to a compound genotype created using this strain.
Contact JAX^® Services jaxservices@jax.org for customized breeding options.

Vhl^tm1Jae/Vhl^tm1Jae Tg(Alb-cre)21Mgn/0

        involves: 129S4/SvJae * BALB/c * C57BL/6 * DBA   (conditional)

• life span-post-weaning/aging
• premature death (MGI Ref ID J:67505)
  • die between 6 and 13 weeks of age
• growth/size phenotype
• decreased body weight (MGI Ref ID J:67505)
  • body weight is about 50% of wild-type
• liver/biliary system phenotype
• abnormal liver morphology (MGI Ref ID J:67505)
  • numerous blood filled vascular cavities, but no large cavernous hemangiomas, are seen
• enlarged liver (MGI Ref ID J:67505)
  • severe
• hepatic steatosis (MGI Ref ID J:97652)
  • severe steatosis
  • accumulation of neutral fats in hepatocytes is detectable by 2 weeks of age
• cardiovascular system phenotype
• abnormal vasculature (MGI Ref ID J:67505)
  • foci of increased vascularization are present in the liver
• increased vascular endothelial cell number (MGI Ref ID J:97652)
  • proliferation of endothelial cells in hepatic blood vessels
• abnormal vasodilation (MGI Ref ID J:97652)
  • hepatic vascular angiectasia
• hematopoietic system phenotype
• polycythemia (MGI Ref ID J:67505)

View Research Applications

Research Applications

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

Research Tools
Cre-lox System (loxP-flanked Sequences)

Vhl^tm1Jae related

Cancer Research
Tumor Suppressor Genes

Genes & Alleles

Gene & Allele Information

Allele Symbol		Vhltm1Jae
Allele Name		targeted mutation 1, Rudolf Jaenisch
Allele Type		Targeted (Floxed/Frt)
Common Name(s)		2-lox allele; VHL2; VHLf; Vhlh 2-lox; Vhlh+f; Vhlh2; Vhlh2lox; Vhlhfl;
Mutation Made By		Rudolf Jaenisch,   Massachusetts Institute of Technology
Strain of Origin		129S4/SvJae
ES Cell Line Name		J1
ES Cell Line Strain		129S4/SvJae
Gene Symbol and Name		Vhl, von Hippel-Lindau syndrome
Chromosome		6
Gene Common Name(s)		HRCA1; RCA1; VHL1; Vhlh; von Hippel-Lindau syndrome homolog;
Molecular Note		A CMV-hyTK selection cassette flanked by two loxP sites was inserted approximately 2.6 kb upstream of exon 1. A third loxP site was inserted into intron 1. The hygromycin cassette was deleted in ES cells by transient transfection with a vector driving expression of Cre recombinase. The resulting ES cell derivatives with two loxP sites flanking exon 1 were selected and injected into blastocysts to generate the Vhlhtm1Jae allele. [MGI Ref ID J:67505]

Genotyping

Genotyping Information

Genotyping Protocols

Vhl^tm1Jae, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Haase VH; Glickman JN; Socolovsky M; Jaenisch R. 2001. Vascular tumors in livers with targeted inactivation of the von Hippel-Lindau tumor suppressor. Proc Natl Acad Sci U S A 98(4):1583-8. [PubMed: 11171994]  [MGI Ref ID J:67505]

Additional References

Vhl^tm1Jae related

Biju MP; Neumann AK; Bensinger SJ; Johnson RS; Turka LA; Haase VH. 2004. Vhlh gene deletion induces hif-1-mediated cell death in thymocytes. Mol Cell Biol 24(20):9038-47. [PubMed: 15456877]  [MGI Ref ID J:93322]

Cramer T; Yamanishi Y; Clausen BE; Forster I; Pawlinski R; Mackman N; Haase VH; Jaenisch R; Corr M; Nizet V; Firestein GS; Gerber HP; Ferrara N; Johnson RS. 2003. HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 112(5):645-57. [PubMed: 12628185]  [MGI Ref ID J:107682]

Ding M; Cui S; Li C; Jothy S; Haase V; Steer BM; Marsden PA; Pippin J; Shankland S; Rastaldi MP; Cohen CD; Kretzler M; Quaggin SE. 2006. Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice. Nat Med 12(9):1081-7. [PubMed: 16906157]  [MGI Ref ID J:115017]

Frew IJ; Minola A; Georgiev S; Hitz M; Moch H; Richard S; Vortmeyer AO; Krek W. 2008. Combined VHLH and PTEN mutation causes genital tract cystadenoma and squamous metaplasia. Mol Cell Biol 28(14):4536-48. [PubMed: 18474617]  [MGI Ref ID J:137442]

Frew IJ; Thoma CR; Georgiev S; Minola A; Hitz M; Montani M; Moch H; Krek W. 2008. pVHL and PTEN tumour suppressor proteins cooperatively suppress kidney cyst formation. EMBO J 27(12):1747-57. [PubMed: 18497742]  [MGI Ref ID J:137073]

Haase VH. 2005. The VHL tumor suppressor in development and disease: functional studies in mice by conditional gene targeting. Semin Cell Dev Biol 16(4-5):564-74. [PubMed: 15908240]  [MGI Ref ID J:101112]

Karhausen J; Furuta GT; Tomaszewski JE; Johnson RS; Colgan SP; Haase VH. 2004. Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis. J Clin Invest 114(8):1098-106. [PubMed: 15489957]  [MGI Ref ID J:93476]

Lei L; Mason S; Liu D; Huang Y; Marks C; Hickey R; Jovin IS; Pypaert M; Johnson RS; Giordano FJ. 2008. Hypoxia-inducible factor-dependent degeneration, failure, and malignant transformation of the heart in the absence of the von Hippel-Lindau protein. Mol Cell Biol 28(11):3790-803. [PubMed: 18285456]  [MGI Ref ID J:136012]

Liu Y; Pop R; Sadegh C; Brugnara C; Haase VH; Socolovsky M. 2006. Suppression of Fas-FasL coexpression by erythropoietin mediates erythroblast expansion during the erythropoietic stress response in vivo. Blood 108(1):123-33. [PubMed: 16527892]  [MGI Ref ID J:135682]

Minamishima YA; Moslehi J; Bardeesy N; Cullen D; Bronson RT; Kaelin WG Jr. 2008. Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure. Blood 111(6):3236-44. [PubMed: 18096761]  [MGI Ref ID J:132718]

Neumann AK; Yang J; Biju MP; Joseph SK; Johnson RS; Haase VH; Freedman BD; Turka LA. 2005. Hypoxia inducible factor 1 alpha regulates T cell receptor signal transduction. Proc Natl Acad Sci U S A 102(47):17071-6. [PubMed: 16286658]  [MGI Ref ID J:103837]

Park SK; Haase VH; Johnson RS. 2007. von Hippel Lindau tumor suppressor regulates hepatic glucose metabolism by controlling expression of glucose transporter 2 and glucose 6-phosphatase. Int J Oncol 30(2):341-8. [PubMed: 17203215]  [MGI Ref ID J:123030]

Peyssonnaux C; Datta V; Cramer T; Doedens A; Theodorakis EA; Gallo RL; Hurtado-Ziola N; Nizet V; Johnson RS. 2005. HIF-1alpha expression regulates the bactericidal capacity of phagocytes. J Clin Invest 115(7):1806-15. [PubMed: 16007254]  [MGI Ref ID J:99628]

Peyssonnaux C; Zinkernagel AS; Schuepbach RA; Rankin E; Vaulont S; Haase VH; Nizet V; Johnson RS. 2007. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest 117(7):1926-32. [PubMed: 17557118]  [MGI Ref ID J:124039]

Pfander D; Kobayashi T; Knight MC; Zelzer E; Chan DA; Olsen BR; Giaccia AJ; Johnson RS; Haase VH; Schipani E. 2004. Deletion of Vhlh in chondrocytes reduces cell proliferation and increases matrix deposition during growth plate development. Development 131(10):2497-508. [PubMed: 15128677]  [MGI Ref ID J:91056]

Rankin EB; Biju MP; Liu Q; Unger TL; Rha J; Johnson RS; Simon MC; Keith B; Haase VH. 2007. Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J Clin Invest 117(4):1068-77. [PubMed: 17404621]  [MGI Ref ID J:121253]

Rankin EB; Higgins DF; Walisser JA; Johnson RS; Bradfield CA; Haase VH. 2005. Inactivation of the arylhydrocarbon receptor nuclear translocator (Arnt) suppresses von Hippel-Lindau disease-associated vascular tumors in mice. Mol Cell Biol 25(8):3163-72. [PubMed: 15798202]  [MGI Ref ID J:97652]

Rankin EB; Rha J; Unger TL; Wu CH; Shutt HP; Johnson RS; Simon MC; Keith B; Haase VH. 2008. Hypoxia-inducible factor-2 regulates vascular tumorigenesis in mice. Oncogene 27(40):5354-8. [PubMed: 18490920]  [MGI Ref ID J:140075]

Rankin EB; Tomaszewski JE; Haase VH. 2006. Renal cyst development in mice with conditional inactivation of the von Hippel-Lindau tumor suppressor. Cancer Res 66(5):2576-83. [PubMed: 16510575]  [MGI Ref ID J:106705]

Shah YM; Ito S; Morimura K; Chen C; Yim SH; Haase VH; Gonzalez FJ. 2008. Hypoxia-inducible factor augments experimental colitis through an MIF-dependent inflammatory signaling cascade. Gastroenterology 134(7):2036-48, 2048.e1-3. [PubMed: 18439915]  [MGI Ref ID J:136664]

Tang N; Mack F; Haase VH; Simon MC; Johnson RS. 2006. pVHL function is essential for endothelial extracellular matrix deposition. Mol Cell Biol 26(7):2519-30. [PubMed: 16537898]  [MGI Ref ID J:106926]

Wan C; Gilbert SR; Wang Y; Cao X; Shen X; Ramaswamy G; Jacobsen KA; Alaql ZS; Eberhardt AW; Gerstenfeld LC; Einhorn TA; Deng L; Clemens TL. 2008. Activation of the hypoxia-inducible factor-1alpha pathway accelerates bone regeneration. Proc Natl Acad Sci U S A 105(2):686-91. [PubMed: 18184809]  [MGI Ref ID J:131088]

Wang Y; Wan C; Deng L; Liu X; Cao X; Gilbert SR; Bouxsein ML; Faugere MC; Guldberg RE; Gerstenfeld LC; Haase VH; Johnson RS; Schipani E; Clemens TL. 2007. The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development. J Clin Invest 117(6):1616-26. [PubMed: 17549257]  [MGI Ref ID J:122021]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX12

Colony Maintenance

Breeding & Husbandry	This strain originated and is maintained on a C;129S background. It is maintained as a homozygote. Coat color expected from breeding:Albino, Agouti
Mating System	Homozygote x Homozygote         (Female x Male)
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 ~nine weeks. Colony sizes do not generally support stringent age specifications for large volumes of mice; however custom orders and larger quantities of mice are easily arranged. Estimated ship dates for all orders provided within 48 hours of 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
	None Available
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.

General Terms and Conditions

See Terms of Use

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

Terms of Use

General Terms and Conditions

Effective September 26, 2007: License Requirements for Strains using Cre-lox Technology only apply in Canada, see Licenses for Strains using Cre-lox Technology.

For additional Licensing and Use Restrictions view the link(s) below:
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Contact information

General inquiries

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

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