Description

Strain Information

Former Names B6.Cg-Vhltm1Jae/J    (Changed: 07-JUL-10 ) 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)   05-OCT-11 Species laboratory mouse Generation N10pN2F5 (19-OCT-12) Generation Definitions   Donating Investigator Jianping Ye,   Pennington Biomedical Research Center

Description
This strain contains loxP sites flanking the Vhl promoter and exon 1. 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.

When bred to a strain expressing Cre recombinase in the myeloid cell lineage (see Stock No. 004781 for example), this mutant mouse strain may be useful in studies of myeloid cell mediated inflammation.

When bred to a strain expressing Cre recombinase in liver (see Stock No. 003574 for example), this mutant mouse strain may be useful in studies of the regulation of hypoxia responsive genes.

When bred to a strain expressing Cre recombinase in the kidney and genitourinary tract (see Stock No. 012237 for example), this mutant mouse strain may be useful in studies of genital pathologies associated with VHL disease.

When bred to a strain expressing Cre recombinase in cardiac muscle cells (Tg(Myh6-cre)2182Mds, see Stock No. 011038 for example), this mutant mouse strain may be useful in studies of cardiomyopathy.

When bred to a strain expressing inducible Cre recombinase in the osteoblast lineage (Tg(Sp7-tTA,tetO-EGFP/cre)1Amc), see Stock No. 006361 for example), this mutant mouse strain may be useful in studies of erythropoiesis.

In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. This is the case for the strain above. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.

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. The strain was maintained on a C;129S background. The mice were then backcrossed to C57BL/6J for 10 generations. Upon arrival at The Jackson Laboratory, the mice were crossed to C57BL/6J (Stock No. 000664) at least once to establish the colony.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls

Related Strains

Strains carrying   Vhl^tm1Jae allele

004081

C;129S-Vhltm1Jae/J

View Strains carrying   Vhl^tm1Jae     (1 strain)

Strains carrying other alleles of Vhl

003123

129S;ICR-Vhltm1Bjg/J

View Strains carrying other alleles of Vhl     (1 strain)

Additional Web Information

Introduction to Cre-lox technology

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Von Hippel-Lindau Syndrome; VHL

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Erythrocytosis, Familial, 2; ECYT2   (VHL) Pheochromocytoma Pheochromocytoma, Susceptibility to   (VHL) Renal Cell Carcinoma, Nonpapillary; RCC   (VHL)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Vhl^tm1Jae/Vhl^tm1Jae

        involves: 129S4/SvJae * BALB/c

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

Vhl^tm1Jae/Vhl^tm1Jae

        involves: 129S4/SvJae

• cellular phenotype
• decreased cell proliferation
  • of MEFs after 48 hours of culturing in normoxia or hypoxia conditions   (MGI Ref ID J:160941)

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 Lyz2^tm1(cre)Ifo/Lyz2⁺

        involves: 129P2/OlaHsd * 129S4/SvJae   (conditional)

• immune system phenotype
• increased inflammatory response
  • TPA-treated ears exhibit increased edema and inflammatory infiltration compared with similarly treated wild-type ears   (MGI Ref ID J:107682)

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

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

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

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

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

• mortality/aging
• premature death
  • mice die at 6 to 8 weeks of age   (MGI Ref ID J:144666)
• liver/biliary system phenotype
• abnormal liver morphology
  • at 6 weeks, the liver is friable and stippled with irregular yellow spots on a reddish black background unlike in wild-type mice   (MGI Ref ID J:144666)
  • hepatic vascularity is increased compared to in wild-type mice   (MGI Ref ID J:144666)
• • abnormal hepatocyte morphology
    • livers contain irregular, dilated, blood filled sinusoids and cytoplasmic vacuolizations within hepatocytes with eccentric nuclei unlike in wild-type mice   (MGI Ref ID J:144666)
  • hepatic steatosis
    • in a mixed micro- and macrovesicular steatotic pattern   (MGI Ref ID J:144666)
  • increased liver weight
    • at 6 weeks of age   (MGI Ref ID J:144666)
• increased hepatocyte proliferation   (MGI Ref ID J:144666)
• hematopoietic system phenotype
• increased hematocrit   (MGI Ref ID J:144666)
• reticulocytosis   (MGI Ref ID J:144666)
• cardiovascular system phenotype
• abnormal blood vessel morphology
  • hepatic vascularity is increased compared to in wild-type mice   (MGI Ref ID J:144666)
• growth/size phenotype
• decreased body size
  • mice are runted   (MGI Ref ID J:144666)
• integument phenotype
• reddish skin
  • of paws and unfurred skin by 4 to 6 weeks of age   (MGI Ref ID J:144666)
• cellular phenotype
• increased hepatocyte proliferation   (MGI Ref ID J:144666)

Vhl^tm1Jae/Vhl^tm1Jae Tg(Cdh16-cre)91Igr/0

        involves: 129S4/SvJae * ICR   (conditional)

• reproductive system phenotype
• abnormal epididymis morphology
  • aberrant presence of dilated blood capillaries surrounding epididymal tubules indicating increased vascularization   (MGI Ref ID J:137442)
  • however, the genital tracts of males and females look normal   (MGI Ref ID J:137442)

Vhl^tm1Jae/Vhl^tm1Jae Tg(Cdh16-cre)91Igr/0

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

• renal/urinary system phenotype
• hydronephrosis
  • hydronephrosis, characterized by an expansion of the renal pelvis   (MGI Ref ID J:137073)
  • however, mutants do not display histological abnormalities in the urothelium of the renal pelvis or ureter, or in the structure of the tubules in the kidney cortex or medulla   (MGI Ref ID J:137073)

Vhl^tm1Jae/Vhl^tm1Jae Tg(Myh6-cre)2182Mds/0

        involves: 129S4/SvJae * FVB/N   (conditional)

• mortality/aging
• premature death
  • mean survival is 9 weeks   (MGI Ref ID J:179490)
• cardiovascular system phenotype
• abnormal heart left ventricle morphology
  • at 8 weeks, mice exhibit reduced left ventricular wall thickness and increased left ventricular end-diastolic dimension compared with control mice   (MGI Ref ID J:179490)
• cardiomyopathy
  • severe at 8 weeks of age   (MGI Ref ID J:179490)
• decreased ventricle muscle contractility
  • at 5 weeks and severe at 8 weeks   (MGI Ref ID J:179490)
• increased angiogenesis   (MGI Ref ID J:179490)
• increased heart weight
  • at 5 weeks and severe at 8 weeks   (MGI Ref ID J:179490)
• muscle phenotype
• cardiomyopathy
  • severe at 8 weeks of age   (MGI Ref ID J:179490)
• decreased ventricle muscle contractility
  • at 5 weeks and severe at 8 weeks   (MGI Ref ID J:179490)
• cellular phenotype
• decreased mitochondria number
  • myocytes exhibit mitochondrial loss   (MGI Ref ID J:179490)

Vhl^tm1Jae/Vhl^tm1Jae Tg(NPHS2-cre)295Lbh/?

        involves: 129S4/SvJae * C57BL/6 * SJL   (conditional)

• mortality/aging
• premature death
  • premature death beginning at ~6 months of age in mice with the highest levels of albuminuria (>1000 ug/ml)   (MGI Ref ID J:162099)
  • however, nonproteinuric mice survive to >1 year of age without overt health problems   (MGI Ref ID J:162099)
• renal/urinary system phenotype
• *normal* renal/urinary system phenotype
  • at P5, all mice exhibit normal comma and S-shaped nephric figures as well as normal capillary loop stage and maturing stage glomeruli relative to wild-type controls   (MGI Ref ID J:162099)
  • no changes in peritubular microvessels or larger arterioles and veins are observed   (MGI Ref ID J:162099)
• • abnormal renal glomerulus basement membrane morphology
    • incompletely fused or fragmented GBM noted on the subendothelial side of the capillary loop in nonproteinuric mice at 4 weeks of age   (MGI Ref ID J:162099)
  • • increased renal glomerulus basement membrane thickness
      • abnormal GBM thickenings with numerous subepithelial "humps" and subendothelial matrix projections noted in nonproteinuric mice at 4 weeks of age   (MGI Ref ID J:162099)
      • at 16 weeks of age, overall GBM thickness in nonproteinuric mice increases to ~100 nm more than in wild-type controls   (MGI Ref ID J:162099)
      • ectopic deposition of collagen alpha1alpha2alpha1(IV) noted in GBM humps beneath podocytes   (MGI Ref ID J:162099)
  • albuminuria
    • at 4 weeks of age, mice exhibit varying levels of albuminuria ranging from no detectable albumin to >1000 ug/ml in severe cases   (MGI Ref ID J:162099)
    • 54% of mice (males and females) are nonproteinuric with albumin levels ranging from 2.9 to 29.7 ug/ml, similar to those in wild-type controls   (MGI Ref ID J:162099)
  • decreased podocyte number
    • significant decrease in podocyte number noted in both proteinuric and nonproteinuric mice at 4 weeks of age, as shown WT1 staining   (MGI Ref ID J:162099)
  • dilated glomerular capillary
    • dilated glomerular capillary lumen noted in mice with severe albuminuria as early as 4 weeks of age   (MGI Ref ID J:162099)
  • dilated kidney collecting duct
    • dilated medullary collecting ducts noted in nonproteinuric mice at 4 weeks of age   (MGI Ref ID J:162099)
  • dilated renal tubules
    • dilated tubules containing proteinaceous casts and cellular debris noted in mice with severe albuminuria at 25 weeks of age   (MGI Ref ID J:162099)
    • occasional dilated tubules in nonproteinuric mice at 4 weeks of age   (MGI Ref ID J:162099)
  • expanded mesangial matrix
    • mesangial matrix expansion noted in mice with severe albuminuria at 4 weeks of age   (MGI Ref ID J:162099)
    • slightly increased mesangial matrix noted in nonproteinuric mice at 4 weeks of age   (MGI Ref ID J:162099)
  • glomerular crescent
    • glomerular crescents noted in mice with severe albuminuria at 4 weeks of age   (MGI Ref ID J:162099)
  • kidney failure
    • end-stage renal failure observed in mice with the highest levels of albuminuria   (MGI Ref ID J:162099)
  • mesangial cell hyperplasia
    • mesangial hypercellularity noted in mice with severe albuminuria at 4 weeks of age   (MGI Ref ID J:162099)
  • podocyte foot process effacement
    • podocyte foot process broadening noted in all nonproteinuric mice at 4 weeks of age   (MGI Ref ID J:162099)
  • renal cast
    • proteinaceous casts detected in dilated tubules of mice with severe albuminuria at 25 weeks of age   (MGI Ref ID J:162099)
    • proteinaceous casts also noted in dilated medullary collecting ducts of nonproteinuric mice at 4 weeks of age   (MGI Ref ID J:162099)
  • renal glomerulus fibrosis
    • severely fibrotic glomeruli noted in mice with massive albuminuria at 25 weeks of age   (MGI Ref ID J:162099)
  • renal interstitial fibrosis
    • noted in mice with severe albuminuria at 25 weeks of age   (MGI Ref ID J:162099)
• homeostasis/metabolism phenotype
• albuminuria
  • at 4 weeks of age, mice exhibit varying levels of albuminuria ranging from no detectable albumin to >1000 ug/ml in severe cases   (MGI Ref ID J:162099)
  • 54% of mice (males and females) are nonproteinuric with albumin levels ranging from 2.9 to 29.7 ug/ml, similar to those in wild-type controls   (MGI Ref ID J:162099)
• edema
  • edema noted in mice with the highest levels of albuminuria   (MGI Ref ID J:162099)
• increased blood urea nitrogen level
  • at 33-41-weeks of age, increased BUN levels are noted in association with only the highest levels of albuminuria (>1000 ug/ml)   (MGI Ref ID J:162099)
  • severely nephrotic mice show a 6-fold increase in BUN levels relative to mice with lower levels of albuminuria   (MGI Ref ID J:162099)
• growth/size phenotype
• cachexia
  • wasting noted in mice with the highest levels of albuminuria   (MGI Ref ID J:162099)
• cardiovascular system phenotype
• dilated glomerular capillary
  • dilated glomerular capillary lumen noted in mice with severe albuminuria as early as 4 weeks of age   (MGI Ref ID J:162099)

Vhl^tm1Jae/Vhl^tm1Jae Tg(Sp7-tTA,tetO-EGFP/cre)1Amc/0

        involves: 129S4/SvJae * CD-1   (conditional)

• hematopoietic system phenotype
• abnormal blood cell morphology/development
  • 3-fold increase in the frequency of KLS cells (hematopoietic stem cells and multipotential progenitors)   (MGI Ref ID J:186085)
• • decreased lymphocyte cell number   (MGI Ref ID J:186085)
  • extramedullary hematopoiesis   (MGI Ref ID J:186085)
  • increased erythrocyte cell number   (MGI Ref ID J:186085)
  • • polycythemia
      • severe by 2 months   (MGI Ref ID J:186085)
  • increased erythroid progenitor cell number
    • 1.4-fold in the bone marrow   (MGI Ref ID J:186085)
    • 4-fold in the spleen   (MGI Ref ID J:186085)
    • increased mature erythroid (CFU-E) compared with immature erythroid (BFU-E)   (MGI Ref ID J:186085)
  • increased hematocrit   (MGI Ref ID J:186085)
• decreased bone marrow cell number   (MGI Ref ID J:186085)
• enlarged spleen   (MGI Ref ID J:186085)
• increased hematopoietic stem cell number   (MGI Ref ID J:186085)
• skeleton phenotype
• increased bone trabecula number   (MGI Ref ID J:186085)
• increased osteoblast cell number
  • increased trabecular osteoblasts   (MGI Ref ID J:186085)
• increased trabecular bone mass
  • in the metaphyseal and diaphyseal regions   (MGI Ref ID J:186085)
• increased trabecular bone volume
  • 2.5-fold in the metaphyseal region   (MGI Ref ID J:186085)
• cardiovascular system phenotype
• abnormal angiogenesis
  • hypervasculatization of the bone   (MGI Ref ID J:186085)
• growth/size phenotype
• decreased body size   (MGI Ref ID J:186085)
• homeostasis/metabolism phenotype
• increased circulating erythropoietin level   (MGI Ref ID J:186085)
• immune system phenotype
• decreased lymphocyte cell number   (MGI Ref ID J:186085)
• enlarged spleen   (MGI Ref ID J:186085)
• limbs/digits/tail phenotype
• abnormal foot pad morphology
  • red paw   (MGI Ref ID J:186085)

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 provided by MGI

Allele Symbol		Vhltm1Jae
Allele Name		targeted mutation 1, Rudolf Jaenisch
Allele Type		Targeted (Floxed/Frt)
Common Name(s)		2-lox allele; VHL+f; VHL2; VHLf; Vhlh 2-lox; Vhlh+f; Vhlh2; Vhlh2lox; Vhlhfl;
Mutation Made By		Dr. Rudolf Jaenisch,   Whitehead Institute (MIT)
Strain of Origin		129S4/SvJae
ES Cell Line Name		J1
ES Cell Line Strain		129S4/SvJae
Gene Symbol and Name		Vhl, von Hippel-Lindau tumor suppressor
Chromosome		6
Gene Common Name(s)		HRCA1; RCA1; VHL1; Vhlh; pVHL; 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 Vhltm1Jae allele. [MGI Ref ID J:67505]

Genotyping

Genotyping Information

Genotyping Protocols

Vhl^tm1Jaealternate1, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

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

Anderson ER; Taylor M; Xue X; Martin A; Moons DS; Omary MB; Shah YM. 2012. The hypoxia-inducible factor-C/EBPalpha axis controls ethanol-mediated hepcidin repression. Mol Cell Biol 32(19):4068-77. [PubMed: 22869521]  [MGI Ref ID J:189135]

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]

Brukamp K; Jim B; Moeller MJ; Haase VH. 2007. Hypoxia and podocyte-specific Vhlh deletion confer risk of glomerular disease. Am J Physiol Renal Physiol 293(4):F1397-407. [PubMed: 17609290]  [MGI Ref ID J:143007]

Cantley J; Selman C; Shukla D; Abramov AY; Forstreuter F; Esteban MA; Claret M; Lingard SJ; Clements M; Harten SK; Asare-Anane H; Batterham RL; Herrera PL; Persaud SJ; Duchen MR; Maxwell PH; Withers DJ. 2009. Deletion of the von Hippel-Lindau gene in pancreatic beta cells impairs glucose homeostasis in mice. J Clin Invest 119(1):125-35. [PubMed: 19065050]  [MGI Ref ID J:144713]

Chan SY; Zhang YY; Hemann C; Mahoney CE; Zweier JL; Loscalzo J. 2009. MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metab 10(4):273-84. [PubMed: 19808020]  [MGI Ref ID J:153662]

Choi D; Cai EP; Schroer SA; Wang L; Woo M. 2011. Vhl is required for normal pancreatic beta cell function and the maintenance of beta cell mass with age in mice. Lab Invest 91(4):527-38. [PubMed: 21242957]  [MGI Ref ID J:170625]

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]

Elorza A; Soro-Arnaiz I; Melendez-Rodriguez F; Rodriguez-Vaello V; Marsboom G; de Carcer G; Acosta-Iborra B; Albacete-Albacete L; Ordonez A; Serrano-Oviedo L; Gimenez-Bachs JM; Vara-Vega A; Salinas A; Sanchez-Prieto R; Martin del Rio R; Sanchez-Madrid F;Malumbres M; Landazuri MO; Aragones J. 2012. HIF2alpha acts as an mTORC1 activator through the amino acid carrier SLC7A5. Mol Cell 48(5):681-91. [PubMed: 23103253]  [MGI Ref ID J:194004]

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]

Hsouna A; Nallamothu G; Kose N; Guinea M; Dammai V; Hsu T. 2010. Drosophila von Hippel-Lindau tumor suppressor gene function in epithelial tubule morphogenesis. Mol Cell Biol 30(15):3779-94. [PubMed: 20516215]  [MGI Ref ID J:162786]

Ikejiri A; Nagai S; Goda N; Kurebayashi Y; Osada-Oka M; Takubo K; Suda T; Koyasu S. 2012. Dynamic regulation of Th17 differentiation by oxygen concentrations. Int Immunol 24(3):137-46. [PubMed: 22207131]  [MGI Ref ID J:182569]

Kapitsinou PP; Liu Q; Unger TL; Rha J; Davidoff O; Keith B; Epstein JA; Moores SL; Erickson-Miller CL; Haase VH. 2010. Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia. Blood 116(16):3039-48. [PubMed: 20628150]  [MGI Ref ID J:165868]

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]

Kim JW; Evans C; Weidemann A; Takeda N; Lee YS; Stockmann C; Branco-Price C; Brandberg F; Leone G; Ostrowski MC; Johnson RS. 2012. Loss of fibroblast HIF-1alpha accelerates tumorigenesis. Cancer Res 72(13):3187-95. [PubMed: 22556263]  [MGI Ref ID J:189318]

Kim WY; Safran M; Buckley MR; Ebert BL; Glickman J; Bosenberg M; Regan M; Kaelin WG Jr. 2006. Failure to prolyl hydroxylate hypoxia-inducible factor alpha phenocopies VHL inactivation in vivo. EMBO J 25(19):4650-62. [PubMed: 16977322]  [MGI Ref ID J:144666]

Kimura K; Iwano M; Higgins DF; Yamaguchi Y; Nakatani K; Harada K; Kubo A; Akai Y; Rankin EB; Neilson EG; Haase VH; Saito Y. 2008. Stable expression of HIF-1alpha in tubular epithelial cells promotes interstitial fibrosis. Am J Physiol Renal Physiol 295(4):F1023-9. [PubMed: 18667485]  [MGI Ref ID J:153791]

Kobayashi H; Gilbert V; Liu Q; Kapitsinou PP; Unger TL; Rha J; Rivella S; Schlondorff D; Haase VH. 2012. Myeloid cell-derived hypoxia-inducible factor attenuates inflammation in unilateral ureteral obstruction-induced kidney injury. J Immunol 188(10):5106-15. [PubMed: 22490864]  [MGI Ref ID J:188688]

Koulnis M; Porpiglia E; Porpiglia PA; Liu Y; Hallstrom K; Hidalgo D; Socolovsky M. 2012. Contrasting dynamic responses in vivo of the Bcl-xL and Bim erythropoietic survival pathways. Blood 119(5):1228-39. [PubMed: 22086418]  [MGI Ref ID J:181805]

Krishnan J; Suter M; Windak R; Krebs T; Felley A; Montessuit C; Tokarska-Schlattner M; Aasum E; Bogdanova A; Perriard E; Perriard JC; Larsen T; Pedrazzini T; Krek W. 2009. Activation of a HIF1alpha-PPARgamma axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy. Cell Metab 9(6):512-24. [PubMed: 19490906]  [MGI Ref ID J:149827]

Kurihara T; Kubota Y; Ozawa Y; Takubo K; Noda K; Simon MC; Johnson RS; Suematsu M; Tsubota K; Ishida S; Goda N; Suda T; Okano H. 2010. von Hippel-Lindau protein regulates transition from the fetal to the adult circulatory system in retina. Development 137(9):1563-71. [PubMed: 20388654]  [MGI Ref ID J:160163]

Kurihara T; Westenskow PD; Krohne TU; Aguilar E; Johnson RS; Friedlander M. 2011. Astrocyte pVHL and HIF-alpha isoforms are required for embryonic-to-adult vascular transition in the eye. J Cell Biol 195(4):689-701. [PubMed: 22084310]  [MGI Ref ID J:178823]

Lange C; Heynen SR; Tanimoto N; Thiersch M; Le YZ; Meneau I; Seeliger MW; Samardzija M; Caprara C; Grimm C. 2011. Normoxic activation of hypoxia-inducible factors in photoreceptors provides transient protection against light-induced retinal degeneration. Invest Ophthalmol Vis Sci 52(8):5872-80. [PubMed: 21447692]  [MGI Ref ID J:181428]

Lange CA; Luhmann UF; Mowat FM; Georgiadis A; West EL; Abrahams S; Sayed H; Powner MB; Fruttiger M; Smith AJ; Sowden JC; Maxwell PH; Ali RR; Bainbridge JW. 2012. Von Hippel-Lindau protein in the RPE is essential for normal ocular growth and vascular development. Development 139(13):2340-50. [PubMed: 22627278]  [MGI Ref ID J:185536]

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 Q; Davidoff O; Niss K; Haase VH. 2012. Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis. J Clin Invest 122(12):4635-44. [PubMed: 23114598]  [MGI Ref ID J:193997]

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; Kaelin WG Jr. 2010. Reactivation of hepatic EPO synthesis in mice after PHD loss. Science 329(5990):407. [PubMed: 20651146]  [MGI Ref ID J:162614]

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]

Minamishima YA; Moslehi J; Padera RF; Bronson RT; Liao R; Kaelin WG Jr. 2009. A feedback loop involving the Phd3 prolyl hydroxylase tunes the mammalian hypoxic response in vivo. Mol Cell Biol 29(21):5729-41. [PubMed: 19720742]  [MGI Ref ID J:153985]

Miro-Murillo M; Elorza A; Soro-Arnaiz I; Albacete-Albacete L; Ordonez A; Balsa E; Vara-Vega A; Vazquez S; Fuertes E; Fernandez-Criado C; Landazuri MO; Aragones J. 2011. Acute Vhl Gene Inactivation Induces Cardiac HIF-Dependent Erythropoietin Gene Expression. PLoS One 6(7):e22589. [PubMed: 21811636]  [MGI Ref ID J:174924]

Moslehi J; Minamishima YA; Shi J; Neuberg D; Charytan DM; Padera RF; Signoretti S; Liao R; Kaelin WG Jr. 2010. Loss of hypoxia-inducible factor prolyl hydroxylase activity in cardiomyocytes phenocopies ischemic cardiomyopathy. Circulation 122(10):1004-16. [PubMed: 20733101]  [MGI Ref ID J:179490]

Neary MT; Mohun TJ; Breckenridge RA. 2012. A mouse model to study the link between hypoxia, long QT interval and sudden infant death syndrome. Dis Model Mech :. [PubMed: 22977222]  [MGI Ref ID J:193425]

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]

Puri S; Cano DA; Hebrok M. 2009. A role for von Hippel-Lindau protein in pancreatic beta-cell function. Diabetes 58(2):433-41. [PubMed: 19033400]  [MGI Ref ID J:146940]

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; Selak MA; Unger TL; Keith B; Liu Q; Haase VH. 2009. Hypoxia-inducible factor 2 regulates hepatic lipid metabolism. Mol Cell Biol 29(16):4527-38. [PubMed: 19528226]  [MGI Ref ID J:151523]

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]

Rankin EB; Wu C; Khatri R; Wilson TL; Andersen R; Araldi E; Rankin AL; Yuan J; Kuo CJ; Schipani E; Giaccia AJ. 2012. The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO. Cell 149(1):63-74. [PubMed: 22464323]  [MGI Ref ID J:186085]

Schietke RE; Hackenbeck T; Tran M; Gunther R; Klanke B; Warnecke CL; Knaup KX; Shukla D; Rosenberger C; Koesters R; Bachmann S; Betz P; Schley G; Schodel J; Willam C; Winkler T; Amann K; Eckardt KU; Maxwell P; Wiesener MS. 2012. Renal tubular HIF-2alpha expression requires VHL inactivation and causes fibrosis and cysts. PLoS One 7(1):e31034. [PubMed: 22299048]  [MGI Ref ID J:184217]

Seagroves TN; Peacock DL; Liao D; Schwab LP; Krueger R; Handorf CR; Haase VH; Johnson RS. 2010. VHL deletion impairs mammary alveologenesis but is not sufficient for mammary tumorigenesis. Am J Pathol 176(5):2269-82. [PubMed: 20382704]  [MGI Ref ID J:160375]

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]

Shah YM; Matsubara T; Ito S; Yim SH; Gonzalez FJ. 2009. Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency. Cell Metab 9(2):152-64. [PubMed: 19147412]  [MGI Ref ID J:145975]

Steenhard BM; Isom K; Stroganova L; St John PL; Zelenchuk A; Freeburg PB; Holzman LB; Abrahamson DR. 2010. Deletion of von Hippel-Lindau in glomerular podocytes results in glomerular basement membrane thickening, ectopic subepithelial deposition of collagen {alpha}1{alpha}2{alpha}1(IV), expression of neuroglobin, and proteinuria. Am J Pathol 177(1):84-96. [PubMed: 20522651]  [MGI Ref ID J:162099]

Takubo K; Goda N; Yamada W; Iriuchishima H; Ikeda E; Kubota Y; Shima H; Johnson RS; Hirao A; Suematsu M; Suda T. 2010. Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell 7(3):391-402. [PubMed: 20804974]  [MGI Ref ID J:164436]

Takubo K; Nagamatsu G; Kobayashi CI; Nakamura-Ishizu A; Kobayashi H; Ikeda E; Goda N; Rahimi Y; Johnson RS; Soga T; Hirao A; Suematsu M; Suda T. 2013. Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. Cell Stem Cell 12(1):49-61. [PubMed: 23290136]  [MGI Ref ID J:194930]

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]

Taylor M; Qu A; Anderson ER; Matsubara T; Martin A; Gonzalez FJ; Shah YM. 2011. Hypoxia-inducible factor-2alpha mediates the adaptive increase of intestinal ferroportin during iron deficiency in mice. Gastroenterology 140(7):2044-55. [PubMed: 21419768]  [MGI Ref ID J:189504]

Theilig F; Enke AK; Scolari B; Polzin D; Bachmann S; Koesters R. 2011. Tubular Deficiency of von Hippel-Lindau Attenuates Renal Disease Progression in Anti-GBM Glomerulonephritis. Am J Pathol 179(5):2177-88. [PubMed: 21925138]  [MGI Ref ID J:177371]

Thorner PS; Ho M; Eremina V; Sado Y; Quaggin S. 2008. Podocytes contribute to the formation of glomerular crescents. J Am Soc Nephrol 19(3):495-502. [PubMed: 18199804]  [MGI Ref ID J:150172]

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]

Weidemann A; Kerdiles YM; Knaup KX; Rafie CA; Boutin AT; Stockmann C; Takeda N; Scadeng M; Shih AY; Haase VH; Simon MC; Kleinfeld D; Johnson RS. 2009. The glial cell response is an essential component of hypoxia-induced erythropoiesis in mice. J Clin Invest 119(11):3373-83. [PubMed: 19809162]  [MGI Ref ID J:154613]

Weidemann A; Krohne TU; Aguilar E; Kurihara T; Takeda N; Dorrell MI; Simon MC; Haase VH; Friedlander M; Johnson RS. 2010. Astrocyte hypoxic response is essential for pathological but not developmental angiogenesis of the retina. Glia 58(10):1177-85. [PubMed: 20544853]  [MGI Ref ID J:168049]

Welford SM; Dorie MJ; Li X; Haase VH; Giaccia AJ. 2010. Renal oxygenation suppresses VHL loss-induced senescence that is caused by increased sensitivity to oxidative stress. Mol Cell Biol 30(19):4595-603. [PubMed: 20679489]  [MGI Ref ID J:164903]

Xue X; Shah YM. 2013. Hypoxia-inducible factor-2alpha is essential in activating the COX2/mPGES-1/PGE2 signaling axis in colon cancer. Carcinogenesis 34(1):163-9. [PubMed: 23042097]  [MGI Ref ID J:193648]

Xue X; Taylor M; Anderson E; Hao C; Qu A; Greenson JK; Zimmermann EM; Gonzalez FJ; Shah YM. 2012. Hypoxia-inducible factor-2alpha activation promotes colorectal cancer progression by dysregulating iron homeostasis. Cancer Res 72(9):2285-93. [PubMed: 22419665]  [MGI Ref ID J:185744]

Young AP; Schlisio S; Minamishima YA; Zhang Q; Li L; Grisanzio C; Signoretti S; Kaelin WG Jr. 2008. VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400. Nat Cell Biol 10(3):361-9. [PubMed: 18297059]  [MGI Ref ID J:145670]

Zehetner J; Danzer C; Collins S; Eckhardt K; Gerber PA; Ballschmieter P; Galvanovskis J; Shimomura K; Ashcroft FM; Thorens B; Rorsman P; Krek W. 2008. pVHL is a regulator of glucose metabolism and insulin secretion in pancreatic {beta} cells. Genes Dev 22(22):3135-46. [PubMed: 19056893]  [MGI Ref ID J:142036]

Zhang J; Wang Y; Gao Z; Yun Z; Ye J. 2012. Hypoxia-inducible factor 1 activation from adipose protein 2-cre mediated knockout of von Hippel-Lindau gene leads to embryonic lethality. Clin Exp Pharmacol Physiol 39(2):145-50. [PubMed: 22150821]  [MGI Ref ID J:196860]

Zhang N; Fu Z; Linke S; Chicher J; Gorman JJ; Visk D; Haddad GG; Poellinger L; Peet DJ; Powell F; Johnson RS. 2010. The asparaginyl hydroxylase factor inhibiting HIF-1alpha is an essential regulator of metabolism. Cell Metab 11(5):364-78. [PubMed: 20399150]  [MGI Ref ID J:160941]

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Breeding & Husbandry	When maintaining a live colony, these mice can be bred as homozygotes.
Mating System	Homozygote x Homozygote         (Female x Male)   05-OCT-11

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