Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Mating System Homozygote x Homozygote         (Female x Male) Species laboratory mouse Generation N6+N1F2 (30-APR-08)   Donating Investigator Randall Johnson,   UC-San Diego

Description
These mice possess loxP sites on either side of exon 2 of the targeted gene. Mice that are homozygous for this allele 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 2 deleted in the cre-expressing tissue(s).

For example, when crossed to a strain expressing Cre recombinase in skeletal and cardiac muscle (see Stock No. 006475), this mutant mouse strain may be useful in studies of the metabolic control of muscle function.

When bred to a strain with the targeted null allele in von Hippel-Lindau syndrome homolog, Vhlh (Stock No. 004081) and a strain expressing Cre recombinase in liver (Stock No. 003574), this mutant mouse strain may be useful in the role of HIF transcription factors in von Hippel-Landau syndrome.

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

Development
Similarly oriented loxP sites were placed upstream of exon 2 and flanking the neomycin resistance cassette (located in intron 2). The construct was electroporated into (129X1/SvJ x 129S1/Sv)F1-derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were transiently transfected with a cre expression plasmid for the purpose of removing the selectable marker cassette. ES cells that had successfully undergone Cre-mediated recombination and no longer retained the cassette but did retain the loxP flanked exon 2 were injected in C57BL/6 blastocysts. Resulting chimeric male animals were backcrossed to wildtype C57BL/6J mice for 12 generations. A speed congenic protocol was used for the first 6 generations of backcrossing, after which the mice were backcrossed an additional 6 generations to C57BL/6J prior to arriving at The Jackson Laboratory. The Y chromosome may not have been fixed to the C57BL/6J genetic background.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls

Additional Web Information

Cre-lox Systems

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

	Glycogen Storage Disease V - Models with phenotypic similarity to human disease where etiologies are distinct.2
	Glycogen Storage Disease VII - Models with phenotypic similarity to human disease where etiologies are distinct.2
	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). 2 Human genes are associated with this disease. Orthologs of those genes do not appear in the mouse genotype(s).

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      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.

Hif1a^tm3Rsjo/Hif1a^tm3Rsjo Vhl^tm1Jae/Vhl^tm1Jae Tg(Alb-cre)21Mgn/0

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

• liver/biliary system phenotype
• hepatic steatosis (MGI Ref ID J:97652)
  • severe steatosis
• cardiovascular system phenotype
• abnormal vasodilation (MGI Ref ID J:97652)
  • hepatic vascular angiectasia
• increased vascular endothelial cell number (MGI Ref ID J:97652)
  • proliferation of endothelial cells in hepatic blood vessels

Hif1a^tm3Rsjo/Hif1a^tm3Rsjo Tg(Ckmm-cre)5Khn/?

        involves: 129S1/Sv * 129X1/SvJ * C57BL/6J * FVB   (conditional)

• muscle phenotype
• abnormal muscle physiology (MGI Ref ID J:97761)
  • increase in muscle damage following exercise
• homeostasis/metabolism phenotype
• abnormal circulating enzyme level (MGI Ref ID J:97761)
  • increased serum levels of the MM isoform of creatine kinase 1 day after exercise
• abnormal exercise endurance (MGI Ref ID J:97761)
  • increased endurance in swim tests and in the first session of running uphill (concentric exercise) but decreased endurance when running downhill (eccentric exercise)
  • endurance decreased over 4 consecutive days of daily treadmill running
• abnormal glucose homeostasis (MGI Ref ID J:97761)
  • significant decrease in lactate accumulation after exercise
• nervous system phenotype
• abnormal muscle innervation (MGI Ref ID J:97761)
  • slight but statistically significant decrease in type IIa fibers in the soleus

Hif1a^tm3Rsjo/Hif1a^tm3Rsjo Tg(UBC-cre/ESR1)1Ejb/0

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

• immune system phenotype
• *normal* immune system phenotype (MGI Ref ID J:119731)
  • hematocrit levels are normal in mutants; mutants do not develop anemia

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)

Genes & Alleles

Gene & Allele Information

Allele Symbol		Hif1atm3Rsjo
Allele Name		targeted mutation 3, Randall S Johnson
Allele Type		Targeted (Floxed/Frt)
Common Name(s)		+f; HIF-1alphaF; HIF1af+; Hif-1alpha 2-lox; Hif1a2lox; Hif1aloxP; Hif+f; Hiff;
Mutation Made By		Randall Johnson,   UC-San Diego
Strain of Origin		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
ES Cell Line Name		R1
ES Cell Line Strain		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
Gene Symbol and Name		Hif1a, hypoxia inducible factor 1, alpha subunit
Chromosome		12
Gene Common Name(s)		AA959795; HIF-1alpha; HIF1; HIF1-ALPHA; HIF1alpha; MOP1; PASD8; expressed sequence AA959795;
Molecular Note		A loxP site was inserted in intron 1 and a floxed neomycin resistance cassette was placed in intron 2. Exon 2 was left flanked by loxP sites after the neo cassette was excised by in vitro expression of cre recombinase. [MGI Ref ID J:78980]

Genotyping

Genotyping Information

Genotyping Protocols

Hif1a^tm3Rsjo, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Ryan HE; Poloni M; McNulty W; Elson D; Gassmann M; Arbeit JM; Johnson RS. 2000. Hypoxia-inducible factor-1alpha is a positive factor in solid tumor growth. Cancer Res 60(15):4010-5. [PubMed: 10945599]  [MGI Ref ID J:78980]

Additional References

Hif1a^tm3Rsjo related

Amarilio R; Viukov SV; Sharir A; Eshkar-Oren I; Johnson RS; Zelzer E. 2007. HIF1{alpha} regulation of Sox9 is necessary to maintain differentiation of hypoxic prechondrogenic cells during early skeletogenesis. Development 134(21):3917-28. [PubMed: 17913788]  [MGI Ref ID J:126336]

Baranova O; Miranda LF; Pichiule P; Dragatsis I; Johnson RS; Chavez JC. 2007. Neuron-specific inactivation of the hypoxia inducible factor 1alpha increases brain injury in a mouse model of transient focal cerebral ischemia. J Neurosci 27(23):6320-32. [PubMed: 17554006]  [MGI Ref ID J:121971]

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]

Chen Y; Doughman YQ; Gu S; Jarrell A; Aota S; Cvekl A; Watanabe M; Dunwoodie SL; Johnson RS; van Heyningen V; Kleinjan DA; Beebe DC; Yang YC. 2008. Cited2 is required for the proper formation of the hyaloid vasculature and for lens morphogenesis. Development 135(17):2939-48. [PubMed: 18653562]  [MGI Ref ID J:139006]

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]

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]

Helton R; Cui J; Scheel JR; Ellison JA; Ames C; Gibson C; Blouw B; Ouyang L; Dragatsis I; Zeitlin S; Johnson RS; Lipton SA; Barlow C. 2005. Brain-specific knock-out of hypoxia-inducible factor-1alpha reduces rather than increases hypoxic-ischemic damage. J Neurosci 25(16):4099-107. [PubMed: 15843612]  [MGI Ref ID J:98637]

Higgins DF; Biju MP; Akai Y; Wutz A; Johnson RS; Haase VH. 2004. Hypoxic induction of Ctgf is directly mediated by Hif-1. Am J Physiol Renal Physiol 287(6):F1223-32. [PubMed: 15315937]  [MGI Ref ID J:95664]

Higgins DF; Kimura K; Bernhardt WM; Shrimanker N; Akai Y; Hohenstein B; Saito Y; Johnson RS; Kretzler M; Cohen CD; Eckardt KU; Iwano M; Haase VH. 2007. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest 117(12):3810-20. [PubMed: 18037992]  [MGI Ref ID J:130751]

Huang Y; Hickey RP; Yeh JL; Liu D; Dadak A; Young LH; Johnson RS; Giordano FJ. 2004. Cardiac myocyte-specific HIF-1alpha deletion alters vascularization, energy availability, calcium flux, and contractility in the normoxic heart. FASEB J 18(10):1138-40. [PubMed: 15132980]  [MGI Ref ID J:118455]

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]

Liao D; Corle C; Seagroves TN; Johnson RS. 2007. Hypoxia-inducible factor-1alpha is a key regulator of metastasis in a transgenic model of cancer initiation and progression. Cancer Res 67(2):563-72. [PubMed: 17234764]  [MGI Ref ID J:117422]

Lukashev D; Klebanov B; Kojima H; Grinberg A; Ohta A; Berenfeld L; Wenger RH; Ohta A; Sitkovsky M. 2006. Cutting edge: hypoxia-inducible factor 1alpha and its activation-inducible short isoform I.1 negatively regulate functions of CD4+ and CD8+ T lymphocytes. J Immunol 177(8):4962-5. [PubMed: 17015677]  [MGI Ref ID J:117857]

Lum JJ; Bui T; Gruber M; Gordan JD; Deberardinis RJ; Covello KL; Simon MC; Thompson CB. 2007. The transcription factor HIF-1{alpha} plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis. Genes Dev 21(9):1037-49. [PubMed: 17437992]  [MGI Ref ID J:121261]

Mason SD; Howlett RA; Kim MJ; Olfert IM; Hogan MC; McNulty W; Hickey RP; Wagner PD; Kahn CR; Giordano FJ; Johnson RS. 2004. Loss of skeletal muscle HIF-1alpha results in altered exercise endurance. PLoS Biol 2(10):e288. [PubMed: 15328538]  [MGI Ref ID J:97761]

Milosevic J; Maisel M; Wegner F; Leuchtenberger J; Wenger RH; Gerlach M; Storch A; Schwarz J. 2007. Lack of hypoxia-inducible factor-1 alpha impairs midbrain neural precursor cells involving vascular endothelial growth factor signaling. J Neurosci 27(2):412-21. [PubMed: 17215402]  [MGI Ref ID J:117302]

Milovanova TN; Bhopale VM; Sorokina EM; Moore JS; Hunt TK; Hauer-Jensen M; Velazquez OC; Thom SR. 2008. Lactate stimulates vasculogenic stem cells via the thioredoxin system and engages an autocrine activation loop involving hypoxia-inducible factor 1. Mol Cell Biol 28(20):6248-61. [PubMed: 18710947]  [MGI Ref ID J:140963]

Morote-Garcia JC; Rosenberger P; Kuhlicke J; Eltzschig HK. 2008. HIF-1-dependent repression of adenosine kinase attenuates hypoxia-induced vascular leak. Blood 111(12):5571-80. [PubMed: 18309031]  [MGI Ref ID J:136635]

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]

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]

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]

Provot S; Zinyk D; Gunes Y; Kathri R; Le Q; Kronenberg HM; Johnson RS; Longaker MT; Giaccia AJ; Schipani E. 2007. Hif-1alpha regulates differentiation of limb bud mesenchyme and joint development. J Cell Biol 177(3):451-64. [PubMed: 17470636]  [MGI Ref ID J:134727]

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; 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]

Rempe D; Vangeison G; Hamilton J; Li Y; Jepson M; Federoff HJ. 2006. Synapsin I Cre transgene expression in male mice produces germline recombination in progeny. Genesis 44(1):44-9. [PubMed: 16419044]  [MGI Ref ID J:105271]

Ritter MR; Banin E; Moreno SK; Aguilar E; Dorrell MI; Friedlander M. 2006. Myeloid progenitors differentiate into microglia and promote vascular repair in a model of ischemic retinopathy. J Clin Invest 116(12):3266-76. [PubMed: 17111048]  [MGI Ref ID J:117348]

Schipani E; Ryan HE; Didrickson S; Kobayashi T; Knight M; Johnson RS. 2001. Hypoxia in cartilage: HIF-1alpha is essential for chondrocyte growth arrest and survival. Genes Dev 15(21):2865-76. [PubMed: 11691837]  [MGI Ref ID J:72709]

Schmidt D; Textor B; Pein OT; Licht AH; Andrecht S; Sator-Schmitt M; Fusenig NE; Angel P; Schorpp-Kistner M. 2007. Critical role for NF-kappaB-induced JunB in VEGF regulation and tumor angiogenesis. EMBO J 26(3):710-9. [PubMed: 17255940]  [MGI Ref ID J:119917]

Seagroves TN; Hadsell D; McManaman J; Palmer C; Liao D; McNulty W; Welm B; Wagner KU; Neville M; Johnson RS. 2003. HIF1alpha is a critical regulator of secretory differentiation and activation, but not vascular expansion, in the mouse mammary gland. Development 130(8):1713-24. [PubMed: 12620994]  [MGI Ref ID J:82618]

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]

Tang N; Wang L; Esko J; Giordano FJ; Huang Y; Gerber HP; Ferrara N; Johnson RS. 2004. Loss of HIF-1alpha in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell 6(5):485-95. [PubMed: 15542432]  [MGI Ref ID J:94773]

Thiel M; Caldwell CC; Kreth S; Kuboki S; Chen P; Smith P; Ohta A; Lentsch AB; Lukashev D; Sitkovsky MV. 2007. Targeted deletion of HIF-1alpha gene in T cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival. PLoS ONE 2(9):e853. [PubMed: 17786224]  [MGI Ref ID J:129383]

Walmsley SR; Print C; Farahi N; Peyssonnaux C; Johnson RS; Cramer T; Sobolewski A; Condliffe AM; Cowburn AS; Johnson N; Chilvers ER. 2005. Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity. J Exp Med 201(1):105-15. [PubMed: 15630139]  [MGI Ref ID J:95245]

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]

Welford SM; Bedogni B; Gradin K; Poellinger L; Broome Powell M; Giaccia AJ. 2006. HIF1alpha delays premature senescence through the activation of MIF. Genes Dev 20(24):3366-71. [PubMed: 17142669]  [MGI Ref ID J:116762]

Xie L; Johnson RS; Freeman RS. 2005. Inhibition of NGF deprivation-induced death by low oxygen involves suppression of BIMEL and activation of HIF-1. J Cell Biol 168(6):911-20. [PubMed: 15767462]  [MGI Ref ID J:98249]

Zelzer E; Mamluk R; Ferrara N; Johnson RS; Schipani E; Olsen BR. 2004. VEGFA is necessary for chondrocyte survival during bone development. Development 131(9):2161-71. [PubMed: 15073147]  [MGI Ref ID J:89363]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX11

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice are bred as homozygotes.
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
	000664 C57BL/6J
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.

---

Ordering and Purchasing Information

      Purchasing Information
      JAX^® Mice Orders
      Surgical Services

Contact Information
Orders & Technical Support
Tel: 800.422.6423 or 207.288.5845
Fax: 207.288.6150
Technical Support Email Form

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.

Contact information

General inquiries

Contracts Administration

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

JAX^® Mice & Services Conditions of Use

“Each recipient institution, including its employees and other researchers under its control (RECIPIENT), of mice or services using mice from The Jackson Laboratory (TJL) agrees that such mice, descendants of those mice derived by inbreeding or crossbreeding, including unmodified derivatives of those mice or their descendants (“MICE”) shall not be: (i) used for any purpose other than the internal research of the RECIPIENT, (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 with respect to MICE. Acceptance of MICE from TJL shall be deemed agreement by RECIPIENT to these conditions, and departure from these conditions requires The Jackson Laboratory’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, The Jackson Laboratory will, at its option, provide credit or replacement for the MICE or product received or the services provided.

No Liability

In no event shall The Jackson Laboratory, 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 The Jackson Laboratory, its agents or employees. In purchasing or receiving MICE, products or services from The Jackson Laboratory, purchaser or recipient, or any party claiming by or through them, expressly releases and discharges The Jackson Laboratory from all such causes of action or damages, and further agrees to defend and indemnify The Jackson Laboratory from any costs or damages arising out of any third party claims.

MICE and biological materials 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 The Jackson Laboratory’s MICE, products and services. In addition, special terms and conditions of sale of certain MICE, products and services may be set forth separately in The Jackson Laboratory 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 The Jackson Laboratory, 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 The Jackson Laboratory, 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 services by The Jackson Laboratory.