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| These D4R-mutant mice harbor a dopamine receptor 4 (Drd4; also called dopamine D4 receptor (D4R)) targeted mutation where exon 2 is replaced with a neomycin resistance cassette, and may be useful in studying dopamine/neurotransmitter function, drug addiction, Parkinson's disease, and schizophrenia or other psychoses. | |||||||||||||||||||
- Description
- Disease & phenotype
- Genes & alleles
- Genotyping
- Health & care
- References
- Pricing & purchasing
- Terms of use
Description
The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.
Strain Information
Type Congenic; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Species laboratory mouse Donating Investigator Dr. Malcolm J Low, University of Michigan Medical School Description
Mice homozygous for this targeted mutation (D4R-/-) are viable and fertile. With exon 2 of the mutant locus deleted, the truncated transcript is predicted to produce a 131 amino acid mutant polypeptide. Homozygous mice may exhibit locomotor supersensitivity to ethanol, cocaine, and methamphetamine, as well as alterations in dopamine synthesis and function, glutamate levels and metabolism, behavioral responses to novelty, and spontaneous locomotor activity in both novel and familiar environments. These D4R-mutant mice may be useful in studying dopamine/neurotransmitter function, drug addiction, Parkinson's disease, and schizophrenia or other psychoses.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. 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 targeting vector was designed to replace exon 2 of the targeted gene with a neomycin resistance cassette. The construct was electroporated into 129P2/OlaHsd-derived E14TG2A embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts, and chimeric males were bred to C57BL/6J females. Heterozygous D4R-mutant mice were bred to wildtype siblings or C57BL/6J mice for approximately 30 generations (including to C57BL/6J for 5 most recent generations) prior to arrival at The Jackson Laboratory. Upon arrival, mice were bred to C57BL/6J for at least one generation to establish the colony.
Control Information
| Control | ||
|---|---|---|
| 000664 C57BL/6J | ||
| Considerations for Choosing Controls | ||
Related Strains
Parkinson's Disease Models
View Parkinson's Disease Models (109 strains)
Additional Web Information
Visit the Parkinson's Disease Resource site for helpful information on Parkinson's and research resources.
Phenotype
Phenotype Information
- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Attention Deficit-Hyperactivity Disorder; ADHD (DRD4)
Novelty Seeking Personality Trait (DRD4)
assigned by genotype
The following phenotype information may relate to a genetic background differing from this JAX® Mice strain.
Drd4tm1Dkg/Drd4tm1Dkg
involves: 129P2/OlaHsd * C57BL/6J
- behavior/neurological phenotype
- *normal* behavior/neurological phenotype
- amphetamine-treated mice exhibit normal reductions in prepulse inhibition and startle reactivity (MGI Ref ID J:55027)
- decreased exploration in new environment
- in the open field test, homozygotes make fewer entries into the center, but do not differ in overall levels of activity relative to wild-type mice (MGI Ref ID J:76023)
- in the emergence test, homozygotes spend more time in the cylinder and make fewer entries into the cylinder relative to wild-type mice (MGI Ref ID J:76023)
- in the novel object test, homozygotes exhibit a smaller increase in % of time spent in the center after introduction of the cup relative to wild-type mice (MGI Ref ID J:76023)
- overall, homozygotes display the largest reductions in behavioral responses to novelty in the test that maximizes approach behaviors (novel object test), and the smallest reductions in the test that maximizes avoidance behavior (open field test) (MGI Ref ID J:76023)
- decreased vertical activity
- homozygotes exhibit fewer rearing episodes in an open field environment relative to wild-type mice (MGI Ref ID J:43061)
- enhanced behavioral response to cocaine
- homozygotes display a dose-dependent hypersensitivity to the locomotor-stimulating effects of cocaine and methamphetamine (MGI Ref ID J:43061)
- enhanced coordination
- homozygotes outperform their wild-type littermates on the rotarod, with 50% fewer falls and a 2.5-fold increase in the length of time remaining on the rotarod (MGI Ref ID J:43061)
- hyperactivity elicited by ethanol administration
- homozygotes are supersensitive to the locomotor-stimulating effects of ethanol (20% v/v) relative wild-type mice (MGI Ref ID J:43061)
- hypoactivity
- impaired behavioral response to addictive substance
- unlike wild-type, catecholamine-depleted, akinetic-rendered homozygotes fail to exhibit a 40% suppression of apomorphine-induced locomotor activity in response to 0.6 mg/kg clozapine (MGI Ref ID J:43061)
- however, both genotypes of mice exhibit complete loss of apomorphine-induced locomotion in response to 6 mg/kg clozapine however, both genotypes of mice exhibit completely loss of apomorphine-induced locomotion in response to 6 mg/kg clozapine (MGI Ref ID J:43061)
- nervous system phenotype
- *normal* nervous system phenotype
- amphetamine-treated mice exhibit normal reductions in prepulse inhibition and startle reactivity (MGI Ref ID J:55027)
- increased dopamine level
- following DOPA decarboxylase inhibition, homozygotes accumulate more L-DOPA in the dorsal striatum-caudate putamen (CPU) relative to wild-type mice (MGI Ref ID J:43061)
- homozygotes exhibit elevated dopamine synthesis and its conversion to DOPAC in the dorsal striatum, as shown by a 93% increase of DOPAC content in CPU and a 1.9-fold increase in DOPAC/DA ratio relative to wild-type mice (MGI Ref ID J:43061)
- homeostasis/metabolism phenotype
- increased dopamine level
- following DOPA decarboxylase inhibition, homozygotes accumulate more L-DOPA in the dorsal striatum-caudate putamen (CPU) relative to wild-type mice (MGI Ref ID J:43061)
- homozygotes exhibit elevated dopamine synthesis and its conversion to DOPAC in the dorsal striatum, as shown by a 93% increase of DOPAC content in CPU and a 1.9-fold increase in DOPAC/DA ratio relative to wild-type mice (MGI Ref ID J:43061)
Drd4tm1Dkg/Drd4tm1Dkg
involves: 129P2/OlaHsd
- vision/eye phenotype
- abnormal eye electrophysiology
- abnormal vision
- optokinetic tracking indicates a decrease in contrast sensitivity over multiple spatial frequencies (MGI Ref ID J:185955)
- behavior/neurological phenotype
- abnormal circadian rhythm
- on day 2 in constant darkness, circadian regulation of the light-adapted electroretinographic response is abolished (MGI Ref ID J:185955)
This mouse can be used to support research in many areas including:
Neurobiology Research
Behavioral and Learning Defects
genes regulating preferences to alcohol
Parkinson's Disease
Receptor Defects
dopamine receptor
Genes & Alleles
Gene & Allele Information provided by MGI
| Allele Symbol | Drd4tm1Dkg | ||
|---|---|---|---|
| Allele Name | targeted mutation 1, David K Grandy | ||
| Allele Type | Targeted (knock-out) | ||
| Common Name(s) | D4-; D4KO; D4R -; Drd4-; | ||
| Mutation Made By | David Grandy, Oregon Heath Sciences University | ||
| Strain of Origin | 129P2/OlaHsd | ||
| ES Cell Line Name | E14TG2a | ||
| ES Cell Line Strain | 129P2/OlaHsd | ||
| Gene Symbol and Name | Drd4, dopamine receptor D4 | ||
| Chromosome | 7 | ||
| Gene Common Name(s) | AW125663; D4DR; D4R; D4RA; Drd-4; expressed sequence AW125663; | ||
| Molecular Note | A neomycin resistance cassette replaced exon 2. RT-PCR analysis demonstrated that a mutated transcript was produced from this allele that spliced exon 1 to exon 3. This mutation causes a shift in the reading frame that is predicted to result in the production of a truncated protein. [MGI Ref ID J:43061] | ||
Genotyping
Genotyping Information
Genotyping Protocols
Drd4tm1Dkg, Standard PCR
Helpful Links
Genotyping resources and troubleshooting
References
References provided by MGI
Selected Reference(s)
Helms CM; Gubner NR; Wilhelm CJ; Mitchell SH; Grandy DK. 2008. D(4) receptor deficiency in mice has limited effects on impulsivity and novelty seeking. Pharmacol Biochem Behav 90(3):387-93. [PubMed: 18456309] [MGI Ref ID J:136871]
Kruzich PJ; Suchland KL; Grandy DK. 2004. Dopamine D4 receptor-deficient mice, congenic on the C57BL/6J background, are hypersensitive to amphetamine. Synapse 53(2):131-9. [PubMed: 15170825] [MGI Ref ID J:136873]
Rubinstein M; Phillips TJ; Bunzow JR; Falzone TL; Dziewczapolski G ; Zhang G ; Fang Y ; Larson JL ; McDougall JA ; Chester JA ; Saez C ; Pugsley TA ; Gershanik O ; Low MJ ; Grandy DK. 1997. Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine. Cell 90(6):991-1001. [PubMed: 9323127] [MGI Ref ID J:43061]
Thomas TC; Grandy DK; Gerhardt GA; Glaser PE. 2008. Decreased Dopamine D4 Receptor Expression Increases Extracellular Glutamate and Alters Its Regulation in Mouse Striatum. Neuropsychopharmacology :. [PubMed: 18536704] [MGI Ref ID J:136870]
Thomas TC; Kruzich PJ; Joyce BM; Gash CR; Suchland K; Surgener SP; Rutherford EC; Grandy DK; Gerhardt GA; Glaser PE. 2007. Dopamine D4 receptor knockout mice exhibit neurochemical changes consistent with decreased dopamine release. J Neurosci Methods 166(2):306-14. [PubMed: 17449106] [MGI Ref ID J:136872]
Additional References
Drd4tm1Dkg relatedBek MJ; Wang X; Asico LD; Jones JE; Zheng S; Li X; Eisner GM; Grandy DK; Carey RM; Soares-da-Silva P; Jose PA. 2006. Angiotensin-II type 1 receptor-mediated hypertension in D4 dopamine receptor-deficient mice. Hypertension 47(2):288-95. [PubMed: 16380537] [MGI Ref ID J:135774]
Cepeda C; Hurst RS; Altemus KL; Flores-Hernandez J; Calvert CR; Jokel ES; Grandy DK; Low MJ; Rubinstein M; Ariano MA; Levine MS. 2001. Facilitated glutamatergic transmission in the striatum of D2 dopamine receptor-deficient mice. J Neurophysiol 85(2):659-70. [PubMed: 11160501] [MGI Ref ID J:103965]
Dulawa SC; Grandy DK; Low MJ; Paulus MP; Geyer MA. 1999. Dopamine D4 receptor-knock-out mice exhibit reduced exploration of novel stimuli. J Neurosci 19(21):9550-6. [PubMed: 10531457] [MGI Ref ID J:76023]
Falzone TL; Gelman DM; Young JI; Grandy DK; Low MJ; Rubinstein M. 2002. Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fear. Eur J Neurosci 15(1):158-64. [PubMed: 11860516] [MGI Ref ID J:89406]
Fan X; Xu M; Hess EJ. 2010. D2 dopamine receptor subtype-mediated hyperactivity and amphetamine responses in a model of ADHD. Neurobiol Dis 37(1):228-36. [PubMed: 19840852] [MGI Ref ID J:156905]
Gan L; Falzone TL; Zhang K; Rubinstein M; Baldessarini RJ; Tarazi FI. 2004. Enhanced expression of dopamine D(1) and glutamate NMDA receptors in dopamine D(4) receptor knockout mice. J Mol Neurosci 22(3):167-78. [PubMed: 14997010] [MGI Ref ID J:121245]
Grady DL; Thanos PK; Corrada MM; Barnett JC Jr; Ciobanu V; Shustarovich D; Napoli A; Moyzis AG; Grandy D; Rubinstein M; Wang GJ; Kawas CH; Chen C; Dong Q; Wang E; Volkow ND; Moyzis RK. 2013. DRD4 genotype predicts longevity in mouse and human. J Neurosci 33(1):286-91. [PubMed: 23283341] [MGI Ref ID J:193918]
Herrmann R; Heflin SJ; Hammond T; Lee B; Wang J; Gainetdinov RR; Caron MG; Eggers ED; Frishman LJ; McCall MA; Arshavsky VY. 2011. Rod vision is controlled by dopamine-dependent sensitization of rod bipolar cells by GABA. Neuron 72(1):101-10. [PubMed: 21982372] [MGI Ref ID J:178532]
Jackson CR; Chaurasia SS; Hwang CK; Iuvone PM. 2011. Dopamine D receptor activation controls circadian timing of the adenylyl cyclase 1/cyclic AMP signaling system in mouse retina. Eur J Neurosci 34(1):57-64. [PubMed: 21676039] [MGI Ref ID J:177942]
Jackson CR; Chaurasia SS; Zhou H; Haque R; Storm DR; Iuvone PM. 2009. Essential roles of dopamine D4 receptors and the type 1 adenylyl cyclase in photic control of cyclic AMP in photoreceptor cells. J Neurochem 109(1):148-57. [PubMed: 19166506] [MGI Ref ID J:149171]
Jackson CR; Ruan GX; Aseem F; Abey J; Gamble K; Stanwood G; Palmiter RD; Iuvone PM; McMahon DG. 2012. Retinal Dopamine Mediates Multiple Dimensions of Light-Adapted Vision. J Neurosci 32(27):9359-9368. [PubMed: 22764243] [MGI Ref ID J:185955]
Katz JL; Chausmer AL; Elmer GI; Rubinstein M; Low MJ; Grandy DK. 2003. Cocaine-induced locomotor activity and cocaine discrimination in dopamine D4 receptor mutant mice. Psychopharmacology (Berl) 170(1):108-14. [PubMed: 12783155] [MGI Ref ID J:103880]
Kvajo M; McKellar H; Gogos JA. 2012. Avoiding mouse traps in schizophrenia genetics: lessons and promises from current and emerging mouse models. Neuroscience 211:136-64. [PubMed: 21821099] [MGI Ref ID J:184660]
Kwon OB; Paredes D; Gonzalez CM; Neddens J; Hernandez L; Vullhorst D; Buonanno A. 2008. Neuregulin-1 regulates LTP at CA1 hippocampal synapses through activation of dopamine D4 receptors. Proc Natl Acad Sci U S A 105(40):15587-92. [PubMed: 18832154] [MGI Ref ID J:143450]
Maison SF; Liu XP; Eatock RA; Sibley DR; Grandy DK; Liberman MC. 2012. Dopaminergic Signaling in the Cochlea: Receptor Expression Patterns and Deletion Phenotypes. J Neurosci 32(1):344-355. [PubMed: 22219295] [MGI Ref ID J:179360]
Michaelides M; Pascau J; Gispert JD; Delis F; Grandy DK; Wang GJ; Desco M; Rubinstein M; Volkow ND; Thanos PK. 2010. Dopamine D4 receptors modulate brain metabolic activity in the prefrontal cortex and cerebellum at rest and in response to methylphenidate. Eur J Neurosci 32(4):668-76. [PubMed: 20646063] [MGI Ref ID J:171781]
Nir I; Harrison JM; Haque R; Low MJ; Grandy DK; Rubinstein M; Iuvone PM. 2002. Dysfunctional light-evoked regulation of cAMP in photoreceptors and abnormal retinal adaptation in mice lacking dopamine D4 receptors. J Neurosci 22(6):2063-73. [PubMed: 11896146] [MGI Ref ID J:75589]
Ogilvie JM; Hakenewerth AM; Gardner RR; Martak JG; Maggio VM. 2009. Dopamine receptor loss of function is not protective of rd1 rod photoreceptors in vivo. Mol Vis 15:2868-78. [PubMed: 20038975] [MGI Ref ID J:157088]
Pozdeyev N; Tosini G; Li L; Ali F; Rozov S; Lee RH; Iuvone PM. 2008. Dopamine modulates diurnal and circadian rhythms of protein phosphorylation in photoreceptor cells of mouse retina. Eur J Neurosci 27(10):2691-700. [PubMed: 18547251] [MGI Ref ID J:137182]
Ralph RJ; Varty GB; Kelly MA; Wang YM; Caron MG; Rubinstein M ; Grandy DK ; Low MJ ; Geyer MA. 1999. The dopamine D2, but not D3 or D4, receptor subtype is essential for the disruption of prepulse inhibition produced by amphetamine in mice. J Neurosci 19(11):4627-33. [PubMed: 10341260] [MGI Ref ID J:55027]
Rubinstein M; Cepeda C; Hurst RS; Flores-Hernandez J; Ariano MA; Falzone TL; Kozell LB; Meshul CK; Bunzow JR; Low MJ; Levine MS; Grandy DK. 2001. Dopamine D4 receptor-deficient mice display cortical hyperexcitability. J Neurosci 21(11):3756-63. [PubMed: 11356863] [MGI Ref ID J:69457]
Seeman P; Weinshenker D; Quirion R; Srivastava LK; Bhardwaj SK; Grandy DK; Premont RT; Sotnikova TD; Boksa P; El-Ghundi M; O'dowd BF; George SR; Perreault ML; Mannisto PT; Robinson S; Palmiter RD; Tallerico T. 2005. Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis. Proc Natl Acad Sci U S A 102(9):3513-8. [PubMed: 15716360] [MGI Ref ID J:96985]
Thanos PK; Habibi R; Michaelides M; Patel UB; Suchland K; Anderson BJ; Robinson JK; Wang GJ; Grandy DK; Volkow ND. 2010. Dopamine D4 receptor (D4R) deletion in mice does not affect operant responding for food or cocaine. Behav Brain Res 207(2):508-11. [PubMed: 19853629] [MGI Ref ID J:156902]
Wang HD; Stanwood GD; Grandy DK; Deutch AY. 2009. Dystrophic dendrites in prefrontal cortical pyramidal cells of dopamine D1 and D2 but not D4 receptor knockout mice. Brain Res 1300:58-64. [PubMed: 19747903] [MGI Ref ID J:157411]
Yuen EY; Zhong P; Yan Z. 2010. Homeostatic regulation of glutamatergic transmission by dopamine D4 receptors. Proc Natl Acad Sci U S A 107(51):22308-13. [PubMed: 21135234] [MGI Ref ID J:167300]
Health & husbandry
The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.
Health & Colony Maintenance Information
Animal Health Reports
Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200.Colony Maintenance
Breeding & Husbandry When maintaining a live colony, homozygous mice may be bred together.
Pricing and Purchasing
Pricing, Supply Level & Notes, Controls
| Pricing for USA, Canada and Mexico shipping destinations |
|
Cryopreserved
Cryopreserved Mice - Ready for Recovery
Animals Provided
Price (US dollars $) Cryorecovery* $1980.00 At least two mice that carry the mutation (if it is a mutant strain) will be provided. Their genotypes may not reflect those discussed in the strain description. Please inquire for possible genotypes and see additional details below.
Standard Supply
Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.
Supply Notes
- Cryorecovery - Standard.
Progeny testing is not required.
The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided, their gender and genotype will vary. We will fulfill your order by providing at least two pair of mice, at least one animal of each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 11 and 14 weeks from the date of your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will ship within 25 weeks. IMPORTANT NOTE: The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.Cryorecovery to establish a Dedicated Supply for greater quantities of mice.
Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 (from U.S.A., Canada or Puerto Rico only) or 1-207-288-5845 (from any location).
| Pricing for International shipping destinations |
|
Cryopreserved
Cryopreserved Mice - Ready for Recovery
Animals Provided
Price (US dollars $) Cryorecovery* $2574.00 At least two mice that carry the mutation (if it is a mutant strain) will be provided. Their genotypes may not reflect those discussed in the strain description. Please inquire for possible genotypes and see additional details below.
Standard Supply
Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.
Supply Notes
- Cryorecovery - Standard.
Progeny testing is not required.
The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided, their gender and genotype will vary. We will fulfill your order by providing at least two pair of mice, at least one animal of each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 11 and 14 weeks from the date of your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will ship within 25 weeks. IMPORTANT NOTE: The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.Cryorecovery to establish a Dedicated Supply for greater quantities of mice.
Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 (from U.S.A., Canada or Puerto Rico only) or 1-207-288-5845 (from any location).
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|
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Standard Supply
Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.
Control Information
| Control | ||
|---|---|---|
| 000664 C57BL/6J | ||
| 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.Ordering Information
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"MICE" means mouse strains, their progeny derived by inbreeding or crossbreeding, unmodified derivatives from mouse strains or their progeny supplied by The Jackson Laboratory ("JACKSON"). "PRODUCTS" means biological materials supplied by JACKSON, and their derivatives. "RECIPIENT" means each recipient of MICE, PRODUCTS, or services provided by JACKSON including each institution, its employees and other researchers under its control. MICE or PRODUCTS shall not be: (i) used for any purpose other than the internal research, (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. Acceptance of MICE or PRODUCTS from JACKSON shall be deemed as agreement by RECIPIENT to these conditions, and departure from these conditions requires JACKSON's prior written authorization.No Warranty
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