Description

Strain Information

Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Mating System Homozygote x Homozygote         (Female x Male) Species laboratory mouse Generation F?+F10N1F5 (27-APR-08)   Donating Investigator Richard Hynes,   Massachusetts Institute of Technology

Description
Mice that are homozygous for this targeted allele are viable and fertile. No gene product (protein) is detected on the surface of platelets. Significant (50%) embryonic lethality attributed to fetal hemorrhaging and placental defects is observed. Until three weeks of age, additional pup loss may occur due to hemorrhaging in the skin and gastrointestinal tract. Gastrointestinal tract bleeding is commonly observed in adults and is frequently associated with an enlarged spleen. Erythrocyte number, hemoglobin, hematocrits and thrombus formation are all reduced while bleeding time is prolonged. Varying degrees of liver and kidney necrosis are also observed. Although increased numbers of osteoclasts are observed (3.5 fold over that seen in heterozygotes) they appear to be dysfunctional, having a reduced ability to resorb whale dentin in vitro. Mice are osteosclerotic and hypocalcemic. Enhanced tumor angiogenesis and vascular endothelial growth factor-induced blood vessel growth are observed. This mutant mouse strain represents a model that may be useful in studies related to Glanzmann thrombasthenia.

Development
A targeting vector containing a neomycin resistance gene driven by the mouse phosphoglycerate kinase promoter was used to disrupt exons 1 and 2 of the targeted gene. The construct was transfected into 129S2/SvPas-derived D3 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting chimeric animals were backcrossed to C57BL/6 mice and made homozygous.

Control Information

	Control
	101045 B6129SF2/J	(approximate)
Considerations for Choosing Controls

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

Glanzmann Thrombasthenia, Autosomal Dominant - 5

5 Conditionally targeted allele(s)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Itgb3^tm1Hyn/Itgb3^tm1Hyn

        involves: 129S2/SvPas * C57BL/6

• lethality-postnatal
• postnatal lethality (MGI Ref ID J:52262)
  • significant loss of homozygous pups up to three weeks of age due to hemorrhage
• life span-post-weaning/aging
• premature death (MGI Ref ID J:52262)
  • some homozygous animals suffered acute blood loss and crisis which lead to premature death
• cardiovascular system phenotype
• hemorrhage (MGI Ref ID J:52262)
  • some homozygous embryos and new born pups displayed hemorrhage in the skin in petechiae and in purpura and appeared anemic
• gastrointestinal hemorrhage (MGI Ref ID J:52262)
  • in some homozygous new born pups which dies before weaning and in many of the remained surviving homozygous adult mice
• uterine hemorrhage (MGI Ref ID J:52262)
• hematopoietic system phenotype
• abnormal platelet activation (MGI Ref ID J:52262)
  • reduced formation of thrombi in Shwartzman-like reaction, an experimental model of hemorrhagic vasculitis induced by subcutaneous injection of LPS followed 24 h later by an injection of TNF-alpha in the same place
  • platelet isolated from homozygous mice did not aggregate after ADP-induced activation in vitro
  • platelet isolated from homozygous mice shows reduced clot retraction and greatly reduced fibrinogen uptake in vitro
• anemia (MGI Ref ID J:52262)
  • secondary to the excessive bleeding
• decreased erythrocyte cell number (MGI Ref ID J:52262)
  • in 8-12-week-old mice
• decreased hematocrit (MGI Ref ID J:52262)
  • in 8-12-week-old mice
• decreased hemoglobin content (MGI Ref ID J:52262)
  • in 8-12-week-old mice
• enlarged spleen (MGI Ref ID J:52262)
  • commonly associated with gastrointestinal bleeding
• extramedullary hematopoiesis (MGI Ref ID J:52262)
  • found in animals with splenomegaly
• reticulocytosis (MGI Ref ID J:52262)
  • in 8-12-week-old mice
• reproductive system phenotype
• abnormal spontaneous abortion rate (MGI Ref ID J:52262)
  • 9.5% of the embryos carried by homozygous mothers were found dead in utero at E14 and E17
• abnormal uterine environment (MGI Ref ID J:52262)
  • compromised survival of embryos in homozygous mother as a result of placental defects and intrauterine hemorrhage
• reduced female fertility (MGI Ref ID J:52262)
  • litter sizes of homozygous female were reduced significantly compared to wild-type
• uterine hemorrhage (MGI Ref ID J:52262)
• embryogenesis phenotype
• abnormal placenta labyrinth morphology (MGI Ref ID J:52262)
  • thickened cell layers in the labyrinth layer in approximately 25% of placentae of homozygous pregnant females which were associated with dead embryos
  • within affected placentae, the space between endothelial layers was reduced with evidence of increased necrosis
• abnormal trophoblast giant cells (MGI Ref ID J:52262)
  • within affected placentae of homozygous pregnant females, trophoblastic cells sometimes invaded the labyrinthine part of the placenta
• pale placenta (MGI Ref ID J:52262)
• digestive/alimentary phenotype
• gastrointestinal hemorrhage (MGI Ref ID J:52262)
  • in some homozygous new born pups which dies before weaning and in many of the remained surviving homozygous adult mice
• immune system phenotype
• dermatitis (MGI Ref ID J:52262)
  • ulcerative dermatitis in some homozygous animals undergoing crisis
• enlarged spleen (MGI Ref ID J:52262)
  • commonly associated with gastrointestinal bleeding
• skin/coat/nails phenotype
• dermatitis (MGI Ref ID J:52262)
  • ulcerative dermatitis in some homozygous animals undergoing crisis
• homeostasis/metabolism phenotype
• abnormal platelet activation (MGI Ref ID J:52262)
  • reduced formation of thrombi in Shwartzman-like reaction, an experimental model of hemorrhagic vasculitis induced by subcutaneous injection of LPS followed 24 h later by an injection of TNF-alpha in the same place
  • platelet isolated from homozygous mice did not aggregate after ADP-induced activation in vitro
  • platelet isolated from homozygous mice shows reduced clot retraction and greatly reduced fibrinogen uptake in vitro
• increased bleeding time (MGI Ref ID J:52262)
  • impaired hemostasis as evidenced by failure to arrest bleeding within 10 minutes following tail resection
• renal/urinary system phenotype
• renal necrosis (MGI Ref ID J:52262)
  • enlarged glomeruli and dilated and necrotic proximal tubules containing proteinaceous deposits are found secondary to the excessive bleeding
• liver/biliary system phenotype
• hepatic necrosis (MGI Ref ID J:52262)
  • centrilobular necrosis of the liver are found secondary to the excessive bleeding
• vision/eye phenotype
• *normal* vision/eye phenotype (MGI Ref ID J:52262)
  • the patterns of neovascularization in P7 retinas isolated from wild-type or homozygous mutant mice showed no obvious differences

View Research Applications

Research Applications

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

Developmental Biology Research
Embryonic Lethality (Homozygous) (incomplete)

Itgb3^tm1Hyn related

Cardiovascular Research
Vascular Defects

Hematological Research
Clotting Defects
Platelet Defects

Genes & Alleles

Gene & Allele Information

Allele Symbol		Itgb3tm1Hyn
Allele Name		targeted mutation 1, Richard O Hynes
Allele Type		Targeted (knock-out)
Common Name(s)		Beta3; beta3 KO; beta3-;
Mutation Made By		Richard Hynes,   Massachusetts Institute of Technology
Strain of Origin		129S2/SvPas
ES Cell Line Name		D3
ES Cell Line Strain		129S2/SvPas
Gene Symbol and Name		Itgb3, integrin beta 3
Chromosome		11
Gene Common Name(s)		CD61; GP3A; GPIIIa; platelet glycoprotein IIIa (GP3A);
Molecular Note		A PGK-neomycin resistance cassette replaced 1.4 kb of sequence including exons I and II. FACS, immunoprecipitation, and immunofluorescence analyses did not detect protein expression in platelets and MEFs from homozygous mutant animals. [MGI Ref ID J:52262]

Genotyping

Genotyping Information

Genotyping Protocols

Itgb3^{tm1 Hyn}, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Hodivala-Dilke KM; McHugh KP; Tsakiris DA; Rayburn H; Crowley D; Ullman-Cullere M; Ross FP; Coller BS; Teitelbaum S; Hynes RO. 1999. Beta3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival. J Clin Invest 103(2):229-38. [PubMed: 9916135]  [MGI Ref ID J:52262]

Additional References

McHugh KP; Hodivala-Dilke K; Zheng MH; Namba N; Lam J; Novack D; Feng X; Ross FP; Hynes RO; Teitelbaum SL. 2000. Mice lacking beta3 integrins are osteosclerotic because of dysfunctional osteoclasts. J Clin Invest 105(4):433-40. [PubMed: 10683372]  [MGI Ref ID J:60672]

Reynolds LE; Wyder L; Lively JC; Taverna D; Robinson SD; Huang X; Sheppard D; Hynes RO; Hodivala-Dilke KM. 2002. Enhanced pathological angiogenesis in mice lacking beta3 integrin or beta3 and beta5 integrins. Nat Med 8(1):27-34. [PubMed: 11786903]  [MGI Ref ID J:73752]

Itgb3^tm1Hyn related

Andre P; Denis CV; Ware J; Saffaripour S; Hynes RO; Ruggeri ZM; Wagner DD. 2000. Platelets adhere to and translocate on von willebrand factor presented by endothelium in stimulated veins Blood 96(10):3322-8. [PubMed: 11071623]  [MGI Ref ID J:65812]

Andre P; Prasad KS; Denis CV; He M; Papalia JM; Hynes RO; Phillips DR; Wagner DD. 2002. CD40L stabilizes arterial thrombi by a beta3 integrin--dependent mechanism. Nat Med 8(3):247-52. [PubMed: 11875495]  [MGI Ref ID J:75152]

Bakewell SJ; Nestor P; Prasad S; Tomasson MH; Dowland N; Mehrotra M; Scarborough R; Kanter J; Abe K; Phillips D; Weilbaecher KN. 2003. Platelet and osteoclast beta3 integrins are critical for bone metastasis. Proc Natl Acad Sci U S A 100(24):14205-10. [PubMed: 14612570]  [MGI Ref ID J:86702]

Bergmeier W; Goerge T; Wang HW; Crittenden JR; Baldwin AC; Cifuni SM; Housman DE; Graybiel AM; Wagner DD. 2007. Mice lacking the signaling molecule CalDAG-GEFI represent a model for leukocyte adhesion deficiency type III. J Clin Invest 117(6):1699-707. [PubMed: 17492052]  [MGI Ref ID J:122618]

Bergmeier W; Piffath CL; Goerge T; Cifuni SM; Ruggeri ZM; Ware J; Wagner DD. 2006. The role of platelet adhesion receptor GPIbalpha far exceeds that of its main ligand, von Willebrand factor, in arterial thrombosis. Proc Natl Acad Sci U S A 103(45):16900-5. [PubMed: 17075060]  [MGI Ref ID J:117137]

Carneiro AM; Cook EH; Murphy DL; Blakely RD. 2008. Interactions between integrin alphaIIbbeta3 and the serotonin transporter regulate serotonin transport and platelet aggregation in mice and humans. J Clin Invest 118(4):1544-52. [PubMed: 18317590]  [MGI Ref ID J:135834]

Chauhan AK; Motto DG; Lamb CB; Bergmeier W; Dockal M; Plaimauer B; Scheiflinger F; Ginsburg D; Wagner DD. 2006. Systemic antithrombotic effects of ADAMTS13. J Exp Med 203(3):767-76. [PubMed: 16533881]  [MGI Ref ID J:123759]

Chun TH; Sabeh F; Ota I; Murphy H; McDonagh KT; Holmbeck K; Birkedal-Hansen H; Allen ED; Weiss SJ. 2004. MT1-MMP-dependent neovessel formation within the confines of the three-dimensional extracellular matrix. J Cell Biol 167(4):757-67. [PubMed: 15545316]  [MGI Ref ID J:94371]

Fang J; Hodivala-Dilke K; Johnson BD; Du LM; Hynes RO; White GC nd; Wilcox DA. 2005. Therapeutic expression of the platelet-specific integrin, alphaIIbbeta3, in a murine model for Glanzmann thrombasthenia. Blood 106(8):2671-9. [PubMed: 15972454]  [MGI Ref ID J:119539]

Feng X; Novack DV; Faccio R; Ory DS; Aya K; Boyer MI; McHugh KP; Ross FP; Teitelbaum SL. 2001. A Glanzmann's mutation in beta 3 integrin specifically impairs osteoclast function. J Clin Invest 107(9):1137-44. [PubMed: 11342577]  [MGI Ref ID J:120522]

Frederix K; Chauhan AK; Kisucka J; Zhao BQ; Hoff EI; Spronk HM; Ten Cate H; Wagner DD. 2007. Platelet adhesion receptors do not modulate infarct volume after a photochemically induced stroke in mice. Brain Res 1185:239-45. [PubMed: 17996853]  [MGI Ref ID J:130124]

Goerge T; Ho-Tin-Noe B; Carbo C; Benarafa C; Remold-O'Donnell E; Zhao BQ; Cifuni SM; Wagner DD. 2008. Inflammation induces hemorrhage in thrombocytopenia. Blood 111(10):4958-64. [PubMed: 18256319]  [MGI Ref ID J:135316]

Hamano Y; Zeisberg M; Sugimoto H; Lively JC; Maeshima Y; Yang C; Hynes RO; Werb Z; Sudhakar A; Kalluri R. 2003. Physiological levels of tumstatin, a fragment of collagen IV alpha3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via alphaV beta3 integrin. Cancer Cell 3(6):589-601. [PubMed: 12842087]  [MGI Ref ID J:120382]

Iannacone M; Sitia G; Isogawa M; Whitmire JK; Marchese P; Chisari FV; Ruggeri ZM; Guidotti LG. 2008. Platelets prevent IFN-alpha/beta-induced lethal hemorrhage promoting CTL-dependent clearance of lymphocytic choriomeningitis virus. Proc Natl Acad Sci U S A 105(2):629-34. [PubMed: 18184798]  [MGI Ref ID J:131089]

Kanamori M; Kawaguchi T; Berger MS; Pieper RO. 2006. Intracranial microenvironment reveals independent opposing functions of host alphaVbeta3 expression on glioma growth and angiogenesis. J Biol Chem 281(48):37256-64. [PubMed: 17028191]  [MGI Ref ID J:117661]

Lacy-Hulbert A; Ueno T; Ito T; Jurewicz M; Izawa A; Smith RN; Chase CM; Tanaka K; Fiorina P; Russell PS; Auchincloss H Jr; Sayegh MH; Hynes RO; Abdi R. 2007. Beta 3 integrins regulate lymphocyte migration and cytokine responses in heart transplant rejection. Am J Transplant 7(5):1080-90. [PubMed: 17359504]  [MGI Ref ID J:134650]

McHugh KP; Hodivala-Dilke K; Zheng MH; Namba N; Lam J; Novack D; Feng X; Ross FP; Hynes RO; Teitelbaum SL. 2000. Mice lacking beta3 integrins are osteosclerotic because of dysfunctional osteoclasts. J Clin Invest 105(4):433-40. [PubMed: 10683372]  [MGI Ref ID J:60672]

Ni H; Chen P; Spring CM; Sayeh E; Semple JW; Lazarus AH; Hynes RO; Freedman J. 2006. A novel murine model of fetal and neonatal alloimmune thrombocytopenia: response to intravenous IgG therapy. Blood 107(7):2976-83. [PubMed: 16317099]  [MGI Ref ID J:131241]

Ni H; Papalia JM; Degen JL; Wagner DD. 2003. Control of thrombus embolization and fibronectin internalization by integrin alpha IIb beta 3 engagement of the fibrinogen gamma chain. Blood 102(10):3609-14. [PubMed: 12855554]  [MGI Ref ID J:86449]

Petrich BG; Fogelstrand P; Partridge AW; Yousefi N; Ablooglu AJ; Shattil SJ; Ginsberg MH. 2007. The antithrombotic potential of selective blockade of talin-dependent integrin alpha IIb beta 3 (platelet GPIIb-IIIa) activation. J Clin Invest 117(8):2250-9. [PubMed: 17627302]  [MGI Ref ID J:123968]

Ren J; Avery J; Zhao H; Schneider JG; Ross FP; Muslin AJ. 2007. Beta3 integrin deficiency promotes cardiac hypertrophy and inflammation. J Mol Cell Cardiol 42(2):367-77. [PubMed: 17184791]  [MGI Ref ID J:119666]

Reynolds AR; Reynolds LE; Nagel TE; Lively JC; Robinson SD; Hicklin DJ; Bodary SC; Hodivala-Dilke KM. 2004. Elevated Flk1 (vascular endothelial growth factor receptor 2) signaling mediates enhanced angiogenesis in beta3-integrin-deficient mice. Cancer Res 64(23):8643-50. [PubMed: 15574772]  [MGI Ref ID J:94450]

Reynolds LE; Conti FJ; Lucas M; Grose R; Robinson S; Stone M; Saunders G; Dickson C; Hynes RO; Lacy-Hulbert A; Hodivala-Dilke K. 2005. Accelerated re-epithelialization in beta(3)-integrin-deficient- mice is associated with enhanced TGF-beta1 signaling. Nat Med 11(2):167-174. [PubMed: 15654327]  [MGI Ref ID J:96049]

Reynolds LE; Wyder L; Lively JC; Taverna D; Robinson SD; Huang X; Sheppard D; Hynes RO; Hodivala-Dilke KM. 2002. Enhanced pathological angiogenesis in mice lacking beta3 integrin or beta3 and beta5 integrins. Nat Med 8(1):27-34. [PubMed: 11786903]  [MGI Ref ID J:73752]

Schulz O; Pennington DJ; Hodivala-Dilke K; Febbraio M; Reis e Sousa C. 2002. CD36 or alphavbeta3 and alphavbeta5 integrins are not essential for MHC class I cross-presentation of cell-associated antigen by CD8 alpha+ murine dendritic cells. J Immunol 168(12):6057-65. [PubMed: 12055214]  [MGI Ref ID J:123797]

Smyth SS; Reis ED; Vaananen H; Zhang W; Coller BS. 2001. Variable protection of beta 3-integrin--deficient mice from thrombosis initiated by different mechanisms. Blood 98(4):1055-62. [PubMed: 11493451]  [MGI Ref ID J:71133]

Svendsen OS; Liden A; Nedrebo T; Rubin K; Reed RK. 2008. Integrin {alpha}v{beta}3 acts downstream of insulin in normalization of interstitial fluid pressure in sepsis and in cell-mediated collagen gel contraction. Am J Physiol Heart Circ Physiol 295(2):H555-60. [PubMed: 18552165]  [MGI Ref ID J:138224]

Taverna D; Crowley D; Connolly M; Bronson RT; Hynes RO. 2005. A direct test of potential roles for beta3 and beta5 integrins in growth and metastasis of murine mammary carcinomas. Cancer Res 65(22):10324-9. [PubMed: 16288021]  [MGI Ref ID J:103405]

Taverna D; Moher H; Crowley D; Borsig L; Varki A; Hynes RO. 2004. Increased primary tumor growth in mice null for beta3- or beta3/beta5-integrins or selectins. Proc Natl Acad Sci U S A 101(3):763-8. [PubMed: 14718670]  [MGI Ref ID J:88109]

Wei C; Moller CC; Altintas MM; Li J; Schwarz K; Zacchigna S; Xie L; Henger A; Schmid H; Rastaldi MP; Cowan P; Kretzler M; Parrilla R; Bendayan M; Gupta V; Nikolic B; Kalluri R; Carmeliet P; Mundel P; Reiser J. 2008. Modification of kidney barrier function by the urokinase receptor. Nat Med 14(1):55-63. [PubMed: 18084301]  [MGI Ref ID J:130835]

Weng S; Zemany L; Standley KN; Novack DV; La Regina M; Bernal-Mizrachi C; Coleman T; Semenkovich CF. 2003. Beta3 integrin deficiency promotes atherosclerosis and pulmonary inflammation in high-fat-fed, hyperlipidemic mice. Proc Natl Acad Sci U S A 100(11):6730-5. [PubMed: 12746502]  [MGI Ref ID J:83615]

Yang H; Reheman A; Chen P; Zhu G; Hynes RO; Freedman J; Wagner DD; Ni H. 2006. Fibrinogen and von Willebrand factor-independent platelet aggregation in vitro and in vivo. J Thromb Haemost 4(10):2230-7. [PubMed: 16824188]  [MGI Ref ID J:129287]

Zhao H; Kitaura H; Sands MS; Ross FP; Teitelbaum SL; Novack DV. 2005. Critical role of beta3 integrin in experimental postmenopausal osteoporosis. J Bone Miner Res 20(12):2116-23. [PubMed: 16294265]  [MGI Ref ID J:128133]

Zhao H; Ross FP; Teitelbaum SL. 2005. Unoccupied alpha(v)beta3 integrin regulates osteoclast apoptosis by transmitting a positive death signal. Mol Endocrinol 19(3):771-80. [PubMed: 15591537]  [MGI Ref ID J:96457]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX12

Colony Maintenance

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

Control Information

	Control
	101045 B6129SF2/J	(approximate)
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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Ordering and Purchasing Information

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Contact Information
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Tel: 800.422.6423 or 207.288.5845
Fax: 207.288.6150
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Terms of Use

Terms of Use

General Terms and Conditions

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

Contact information

General inquiries

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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.”

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