Description

Strain Information

Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Mating System Homozygote x Homozygote         (Female x Male)   01-JUL-09 Species laboratory mouse Generation F?+F6 (06-NOV-08) Generation Definitions   Donating Investigator Celeste Simon,   University of Pennsylvania

Description
The Hif-2α 2-loxP allele, also called Hif-2&alpha^fl or Epas1^2lox, contains loxP sites flanking exon 2 of the endothelial PAS domain protein 1 locus (Epas1 or Hif-2α). Homozygous mice are are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. When these mutant mice are bred to mice that express Cre recombinase, resulting offspring will have exon deleted in the cre-expressing tissue(s).

For example, when bred to a strain with inducible Cre recombinase expression in cardiac cells (see Stock No. 005657 for example), this mutant mouse strain may be useful in studies of erythropoiesis.

When bred to a strain with tamoxifen inducible widespread Cre recombinase expression(see Stock No. 008085 for example), this mutant mouse strain may be useful in studies of erythropoiesis.

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.

Development
A targeting vector was designed to insert a loxP site upstream of exon 2, as well as a loxP-flanked PGK-Neo cassette (in reverse orientation) just downstream of exon 2 of the endothelial PAS domain protein 1 locus (Epas1 or Hif-2α). This construct was electroporated into 129X1/SvJ derived RW-4 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. Chimeric animals were bred to EIIa-Cre transgenic mice (on the C57BL/6 genetic background). The resulting offspring with the PGK-Neo cassette removed and exon 2 flanked by loxP sites were identified (and called Hif-2α 2-loxP, Hif-2&alpha^fl or Epas1^2lox). These Hif-2α 2-loxP mice were then bred with wildtype C57BL/6 to remove the EIIa-Cre transgene. Heterozygous Hif-2α 2-loxP mice were bred together to generate homozygotes prior to sending to The Jackson Laboratory Repository. Upon arrival, mice were bred to C57BL/6J inbred mice (Stock No. 000664) for at least one generation to establish the colony.

Control Information

	Control
	None Available
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Epas1

003266

B6;129S7-Epas1tm1Rus/J

View Strains carrying other alleles of Epas1     (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

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Erythrocytosis, Familial, 4; ECYT4   (EPAS1)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

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

Epas1^tm1Mcs/Epas1^tm1.1Mcs Tg(UBC-cre/ERT2)1Ejb/0

        involves: 129X1/SvJ * FVB/N   (conditional)

• hematopoietic system phenotype
• abnormal hematopoietic system physiology
  • mice show weak induction of erythropoietin after phenylhydrazine treatment   (MGI Ref ID J:119731)
• abnormal proerythroblast morphology
  • erythroid progenitors from bone marrow form ~50% fewer erythroid burst-forming units (BFU-E) and colony-forming units (CFU-E) in culture than control cells, whereas erythroid progenitors from the spleen form more BFU-E and CFU-E   (MGI Ref ID J:119731)
  • there are fewer CD71+ immature erythroid progenitors in the bone marrow, and a higher percentage of CD71+ /Ter119+ double positive cells in the spleen   (MGI Ref ID J:119731)
• anemia
  • occurs after postnatal cre induction   (MGI Ref ID J:119731)
• decreased erythrocyte cell number
  • with acute deletion of Epas1 at 6-8 weeks induced by tamoxifen administration, animals have decreased red blood cell numbers relative to controls   (MGI Ref ID J:119731)
• decreased hematocrit
  • with acute deletion of Epas1 at 6-8 weeks induced by tamoxifen administration, animals have decreased hematocrit relative to controls   (MGI Ref ID J:119731)
• decreased hemoglobin content
  • with acute deletion of Epas1 at 6-8 weeks induced by tamoxifen administration, animals have decreased hemoglobin levels relative to controls   (MGI Ref ID J:119731)
• enlarged spleen
  • spleens are enlarged relative to controls (0.5% spleen weight to body weight vs. ~0.4% in controls)   (MGI Ref ID J:119731)
• reticulocytopenia
  • numbers are decreased compared to controls   (MGI Ref ID J:119731)
• immune system phenotype
• enlarged spleen
  • spleens are enlarged relative to controls (0.5% spleen weight to body weight vs. ~0.4% in controls)   (MGI Ref ID J:119731)

Epas1^tm1Mcs/Epas1^tm1Mcs Tg(Sp7-tTA,tetO-EGFP/cre)1Amc/0

        involves: 129S1/Sv * 129X1/SvJ * CD-1   (conditional)

• hematopoietic system phenotype
• decreased erythroid progenitor cell number
  • decreased frequency of CD71+/Ter119+ cells in the bone marrow   (MGI Ref ID J:186085)

View Research Applications

Research Applications

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

Neurobiology Research
Cre-lox System
      loxP-flanked Sequences

Research Tools
Cardiovascular Research
      Cre-lox System
Cre-lox System
      loxP-flanked Sequences

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Epas1tm1Mcs
Allele Name		targeted mutation 1, M Celeste Simon
Allele Type		Targeted (Floxed/Frt)
Common Name(s)		Epas12lox; HIF-2alpha+f; Hif-2alpha 2-lox; Hif-2alphafl;
Mutation Made By		Celeste Simon,   University of Pennsylvania
Strain of Origin		129X1/SvJ
ES Cell Line Name		RW-4
ES Cell Line Strain		129X1/SvJ
Gene Symbol and Name		Epas1, endothelial PAS domain protein 1
Chromosome		17
Gene Common Name(s)		ECYT4; HIF-2alpha; HIF2A; HLF; HRF; Hif like protein; MOP2; PASD2; bHLHe73; hypoxia inducible transcription factor 2alpha;
Molecular Note		Exon 2 was flanked with loxP sites. [MGI Ref ID J:119731]

Genotyping

Genotyping Information

Genotyping Protocols

Epas1^tm1Mcs, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Gruber M; Hu CJ; Johnson RS; Brown EJ; Keith B; Simon MC. 2007. Acute postnatal ablation of Hif-2alpha results in anemia. Proc Natl Acad Sci U S A 104(7):2301-6. [PubMed: 17284606]  [MGI Ref ID J:119731]

Additional References

Epas1^tm1Mcs related

Araldi E; Khatri R; Giaccia AJ; Simon MC; Schipani E. 2011. Lack of HIF-2alpha in limb bud mesenchyme causes a modest and transient delay of endochondral bone development. Nat Med 17(1):25-6; author reply 27-9. [PubMed: 21217667]  [MGI Ref ID J:168583]

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]

Fang HY; Hughes R; Murdoch C; Coffelt SB; Biswas SK; Harris AL; Johnson RS; Imityaz HZ; Simon MC; Fredlund E; Greten FR; Rius J; Lewis CE. 2009. Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia. Blood 114(4):844-59. [PubMed: 19454749]  [MGI Ref ID J:150747]

Franke K; Kalucka J; Mamlouk S; Singh RP; Muschter A; Weidemann A; Iyengar V; Jahn S; Wieczorek K; Geiger K; Muders M; Sykes AM; Poitz DM; Ripich T; Otto T; Bergmann S; Breier G; Baretton G; Fong GH; Greaves DR; Bornstein S; Chavakis T; Fandrey J; Gassmann M; Wielockx B. 2013. HIF-1alpha is a protective factor in conditional PHD2-deficient mice suffering from severe HIF-2alpha-induced excessive erythropoiesis. Blood 121(8):1436-45. [PubMed: 23264599]  [MGI Ref ID J:194598]

Glick D; Zhang W; Beaton M; Marsboom G; Gruber M; Simon MC; Hart J; Dorn GW 2nd; Brady MJ; Macleod KF. 2012. BNip3 regulates mitochondrial function and lipid metabolism in the liver. Mol Cell Biol 32(13):2570-84. [PubMed: 22547685]  [MGI Ref ID J:186671]

Gruber M; Mathew LK; Runge AC; Garcia JA; Simon MC. 2010. EPAS1 Is Required for Spermatogenesis in the Postnatal Mouse Testis. Biol Reprod 82(6):1227-36. [PubMed: 20181618]  [MGI Ref ID J:161980]

Imtiyaz HZ; Williams EP; Hickey MM; Patel SA; Durham AC; Yuan LJ; Hammond R; Gimotty PA; Keith B; Simon MC. 2010. Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation. J Clin Invest 120(8):2699-714. [PubMed: 20644254]  [MGI Ref ID J:163764]

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]

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]

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]

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; Bravo S; Aguilar E; Friedlander M. 2012. Targeted deletion of Vegfa in adult mice induces vision loss. J Clin Invest 122(11):4213-7. [PubMed: 23093773]  [MGI Ref ID J:194014]

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]

Mastrogiannaki M; Matak P; Delga S; Deschemin JC; Vaulont S; Peyssonnaux C. 2012. Deletion of HIF-2alpha in the enterocytes decreases the severity of tissue iron loading in hepcidin knockout mice. Blood 119(2):587-90. [PubMed: 22128145]  [MGI Ref ID J:181769]

Mastrogiannaki M; Matak P; Keith B; Simon MC; Vaulont S; Peyssonnaux C. 2009. HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice. J Clin Invest 119(5):1159-66. [PubMed: 19352007]  [MGI Ref ID J:149590]

Mazumdar J; Hickey MM; Pant DK; Durham AC; Sweet-Cordero A; Vachani A; Jacks T; Chodosh LA; Kissil JL; Simon MC; Keith B. 2010. HIF-2alpha deletion promotes Kras-driven lung tumor development. Proc Natl Acad Sci U S A 107(32):14182-7. [PubMed: 20660313]  [MGI Ref ID J:163616]

Pourvali K; Matak P; Latunde-Dada GO; Solomou S; Mastrogiannaki M; Peyssonnaux C; Sharp PA. 2012. Basal expression of copper transporter 1 in intestinal epithelial cells is regulated by hypoxia-inducible factor 2alpha. FEBS Lett 586(16):2423-7. [PubMed: 22684009]  [MGI Ref ID J:186999]

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; 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; 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]

Rasbach KA; Gupta RK; Ruas JL; Wu J; Naseri E; Estall JL; Spiegelman BM. 2010. PGC-1{alpha} regulates a HIF2{alpha}-dependent switch in skeletal muscle fiber types. Proc Natl Acad Sci U S A :. [PubMed: 21106753]  [MGI Ref ID J:167144]

Riddle RC; Leslie JM; Gross TS; Clemens TL. 2011. Hypoxia-inducible Factor-1alpha Protein Negatively Regulates Load-induced Bone Formation. J Biol Chem 286(52):44449-56. [PubMed: 22081627]  [MGI Ref ID J:178824]

Shomento SH; Wan C; Cao X; Faugere MC; Bouxsein ML; Clemens TL; Riddle RC. 2010. Hypoxia-inducible factors 1alpha and 2alpha exert both distinct and overlapping functions in long bone development. J Cell Biochem 109(1):196-204. [PubMed: 19899108]  [MGI Ref ID J:161255]

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]

Weigert A; Weichand B; Sekar D; Sha W; Hahn C; Mora J; Ley S; Essler S; Dehne N; Brune B. 2012. HIF-1alpha is a negative regulator of plasmacytoid DC development in vitro and in vivo. Blood 120(15):3001-6. [PubMed: 22936665]  [MGI Ref ID J:192921]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX12

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice can be bred as homozygotes.
Mating System	Homozygote x Homozygote         (Female x Male)   01-JUL-09
Diet Information	LabDiet® 5K52/5K67

Pricing and Purchasing

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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.

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