Description

Strain Information

Type Congenic; Mutant Strain; Spontaneous Mutation; Additional information on Genetically Engineered Mutant Mice. Mating System Heterozygote x Heterozygote         (Female x Male) Species laboratory mouse Background Strain C57BL/6J Generation F?+F19 (22-JAN-08)

Appearance
black, fat
Related Genotype: a/a Cpe^fat/Cpe^fat

black, unaffected
Related Genotype: a/a +/+ or a/a Cpe^fat/+

Description
Mice homozygous for the fat spontaneous mutation (Cpe^fat) on a C57BL/6J genetic background (N10) become noticeably obese by 14-15 weeks of age. There is also some sexual dimorphism; female homozygous mutant mice develop obesity at a later age than males. Cpe^fat mice actually weigh less than wildtype controls prior to weaning age. Homozygous mutant mice develop a diabetic phenotype characterized by hyperglycemia and insulin resistance. Cpe^fat mice appear healthier on the C57BL/6J genetic background, avoiding the hereditary hydronephrosis present in C57BLKS/J and a lower incidence of malocclusion.

Development
The Cpe^fat mutation arose on HRS/J (Hummel et al., 1974).

Control Information

	Control
	Heterozygote from the colony
	Wild-type from the colony
Considerations for Choosing Controls

Related Strains

Strains carrying   Cpe^fat allele

002391	BKSChpLt.HRS-Cpefat/J
003774	CAST.HRS(BKS)-Cpefat/Jng

View Strains carrying   Cpe^fat     (2 strains)

Strains carrying other alleles of Cpe

003713

B6.CAST-Cpe+/J

View Strains carrying other alleles of Cpe     (1 strain)

Additional Web Information

Congenic Nomenclature
JAX^® NOTES, Summer 2002; 486. New Cpe^fat Mouse Model for Diabetes and Obesity Research.

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

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

Cpe^fat/Cpe^fat

        HRS/J

• adipose tissue phenotype
• increased adipose tissue amount (MGI Ref ID J:10872)
  • noted in all adipose tissue of the body
• digestive/alimentary phenotype
• abnormal islet of Langerhans morphology (MGI Ref ID J:10872)
  • hypertrophy and hyperplasia of islets noted
• abnormal pancreatic beta cell morphology (MGI Ref ID J:10872)
  • some degranulation of beta cells was noted
• islet cell hyperplasia (MGI Ref ID J:13651)
  • increased numbers of islets noted
• endocrine/exocrine gland phenotype
• abnormal islet of Langerhans morphology (MGI Ref ID J:10872)
  • hypertrophy and hyperplasia of islets noted
• abnormal pancreatic beta cell morphology (MGI Ref ID J:10872)
  • some degranulation of beta cells was noted
• islet cell hyperplasia (MGI Ref ID J:13651)
  • increased numbers of islets noted
• growth/size phenotype
• obese (MGI Ref ID J:10872)
  • abnormal amounts of fat by 4-5 weeks of age; progressive with age; homozygotes weigh up to 60-70 grams by 6-8 months of age
• homeostasis/metabolism phenotype
• hyperglycemia (MGI Ref ID J:10872)
  • transient hyperglycemia noted in males at 7-8 weeks of age
• hypoglycemia (MGI Ref ID J:13651)
  • fluctuations in blood sugar concentrations occur; concentrations of less than 100mg/100ml are common in animals older than 6 months
• increased circulating insulin level (MGI Ref ID J:13651)
  • severe at weaning age
• reproductive system phenotype
• infertility (MGI Ref ID J:10872)
  • noted in older mice; mice are not sterile; homozygous mice can produce litters if mated before the onset of obesity

Cpe^fat/Cpe^fat

        BKSChpLt.HRS-Cpe^fat/J

• adipose tissue phenotype
• increased adipose tissue amount (MGI Ref ID J:10872)
  • noted in all adipose tissue of the body
• digestive/alimentary phenotype
• abnormal islet of Langerhans morphology (MGI Ref ID J:10872)
  • hypertrophy and hyperplasia of islets noted
• abnormal pancreatic beta cell morphology (MGI Ref ID J:10872)
  • some degranulation of beta cells was noted
  • the presence of immature secretory granules was noted
• decreased digestive secretion (MGI Ref ID J:52393)
  • reduced gastric acid secretion and challenged gastrin release
• endocrine/exocrine gland phenotype
• abnormal hypothalamus secretion (MGI Ref ID J:80698)
  • deficient processing and unregulated secretion of pro-thyrotrophin releasing hormone
• abnormal islet of Langerhans morphology (MGI Ref ID J:10872)
  • hypertrophy and hyperplasia of islets noted
• abnormal pancreatic beta cell morphology (MGI Ref ID J:10872)
  • some degranulation of beta cells was noted
  • the presence of immature secretory granules was noted
• hypersecretion of adrenocorticotropin (MGI Ref ID J:40372)
• growth/size phenotype
• obese (MGI Ref ID J:10872)
  • abnormal amounts of fat by 4-5 weeks of age; progressive with age; homozygotes weigh up to 60-70 grams by 6-8 months of age
• homeostasis/metabolism phenotype
• abnormal body temperature regulation (MGI Ref ID J:80698)
  • homozygous mice cannot maintain the core body temperature upon exposure to cold temperature
• hyperglycemia (MGI Ref ID J:10872)
  • transient hyperglycemia noted in males at 7-8 weeks of age
  • does not progress to severe diabetes
• increased circulating cholesterol level (MGI Ref ID J:18161)
  • increased by 50% over controls
  • noted on a high fat diet compared to controls
• increased circulating HDL cholesterol level (MGI Ref ID J:18161)
  • increased 2 fold over controls
  • noted on a high fat diet compared to controls
• increased circulating LDL cholesterol level (MGI Ref ID J:19043)
  • noted on a high fat diet compared to controls
• increased circulating VLDL cholesterol level (MGI Ref ID J:19043)
  • noted on a high fat diet compared to controls
• increased circulating insulin level (MGI Ref ID J:10872)
  • severe at weaning age
  • hyperproinsulinemia was noted; a defect in hormone processing was demonstrated in vitro
• increased circulating pituitary hormone level (MGI Ref ID J:38227)
  • unregulated secretion of unprocessed pro-opiomelanocortin
• increased circulating adrenocorticotropin level (MGI Ref ID J:40372)
• increased circulating triglyceride level (MGI Ref ID J:19043)
  • noted on a high fat diet compared to controls
• increased pituitary hormone level (MGI Ref ID J:40372)
  • 24 fold increase in unprocessed pro-opiomelanocortin levels in the pituitary; poor processing to adrenocorticotropin and unregulated secretion of the unprocessed hormone
• increased circulating adrenocorticotropin level (MGI Ref ID J:40372)
• reproductive system phenotype
• infertility (MGI Ref ID J:10872)
  • noted in older obese mice; homozygous mice can produce litters if mated before the onset of obesity
• nervous system phenotype
• abnormal hypothalamus secretion (MGI Ref ID J:80698)
  • deficient processing and unregulated secretion of pro-thyrotrophin releasing hormone
• hypersecretion of adrenocorticotropin (MGI Ref ID J:40372)

View Research Applications

Research Applications

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

Cpe^fat related

Diabetes and Obesity Research
Hyperglycemia (males)
Hyperinsulinemia
Impaired Insulin Processing
Insulin Resistance
Obesity With Diabetes (adult onset)
Type 2 Diabetes (NIDDM) (males)

Endocrine Deficiency Research
Adipose Defects
Hypothalamus/Pituitary Defects
Pancreas Defects

Internal/Organ Research
Adipose Defects

Metabolism Research

Reproductive Biology Research
Fertility Defects

Genes & Alleles

Gene & Allele Information

Allele Symbol		Cpefat
Allele Name		fat
Allele Type		Spontaneous
Common Name(s)		fat;
Strain of Origin		HRS/J
Gene Symbol and Name		Cpe, carboxypeptidase E
Chromosome		8
Gene Common Name(s)		CARBE; CPH; Cph-1; Cph1; MGC93638; R74677; carboxypeptidase H; expressed sequence R74677; fat;
Molecular Note		The molecular mutation responsible for the phenotype in the fat mouse is a T to C transition at nucleotide 729 of the mRNA. The codon of this nucleotide corresponds to amino acid 244 of the unprocessed preproenzyme or amino acid 202 of the mature peptidase. The mutation is predicted to alter a conserved serine to a proline residue in the encoded protein. Enzymatic activity of the mutant protein was shown to be abolished in fluorometric assays in vitro. [MGI Ref ID J:24436]

Genotyping

Genotyping Information

Genotyping Protocols

Cpe^fat, EP, vers. 4
Cpe^fat, HRM, vers. 5
Cpe^fat, REST, vers. 3

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Coleman DL; Eicher EM. 1990. Fat (fat) and tubby (tub): two autosomal recessive mutations causing obesity syndromes in the mouse. J Hered 81(6):424-7. [PubMed: 2250094]  [MGI Ref ID J:10872]

Naggert JK; Fricker LD; Varlamov O; Nishina PM; Rouille Y; Steiner DF; Carroll RJ; Paigen BJ; Leiter EH. 1995. Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. Nat Genet 10(2):135-42. [PubMed: 7663508]  [MGI Ref ID J:24436]

Weide LG; Lacy PE. 1991. Hereditary hydronephrosis in C57BL/KsJ mice. Lab Anim Sci 41(5):415-8. [PubMed: 1666139]  [MGI Ref ID J:2848]

Additional References

Cool DR; Normant E; Shen F; Chen HC; Pannell L; Zhang Y; Loh YP. 1997. Carboxypeptidase E is a regulated secretory pathway sorting receptor: genetic obliteration leads to endocrine disorders in Cpe(fat) mice. Cell 88(1):73-83. [PubMed: 9019408]  [MGI Ref ID J:38227]

Cpe^fat related

Berk PD; Zhou S; Kiang C; Stump DD; Fan X; Bradbury MW. 1999. Selective up-regulation of fatty acid uptake by adipocytes characterizes both genetic and diet-induced obesity in rodents. J Biol Chem 274(40):28626-31. [PubMed: 10497230]  [MGI Ref ID J:57965]

Berman Y; Mzhavia N; Polonskaia A; Devi LA. 2001. Impaired prohormone convertases in Cpe(fat)/Cpe(fat) mice. J Biol Chem 276(2):1466-73. [PubMed: 11038363]  [MGI Ref ID J:66910]

Bouchard G; Johnson D; Carver T; Paigen B; Carey MC. 2002. Cholesterol gallstone formation in overweight mice establishes that obesity per se is not linked directly to cholelithiasis risk. J Lipid Res 43(7):1105-13. [PubMed: 12091495]  [MGI Ref ID J:88773]

Cain BM; Wang W; Beinfeld MC. 1997. Cholecystokinin (CCK) levels are greatly reduced in the brains but not the duodenums of Cpe(fat)/Cpe(fat) mice: a regional difference in the involvement of carboxypeptidase E (Cpe) in pro-CCK processing. Endocrinology 138(9):4034-7. [PubMed: 9275097]  [MGI Ref ID J:42848]

Che FY; Yan L; Li H; Mzhavia N; Devi LA; Fricker LD. 2001. Identification of peptides from brain and pituitary of Cpe(fat)/Cpe(fat) mice. Proc Natl Acad Sci U S A 98(17):9971-6. [PubMed: 11481435]  [MGI Ref ID J:71090]

Chiellini C; Costa M; Novelli SE; Amri EZ; Benzi L; Bertacca A; Cohen P; Del Prato S; Friedman JM; Maffei M. 2003. Identification of cathepsin K as a novel marker of adiposity in white adipose tissue. J Cell Physiol 195(2):309-21. [PubMed: 12652657]  [MGI Ref ID J:106181]

Chiu CH; Lin WD; Huang SY; Lee YH. 2004. Effect of a C/EBP gene replacement on mitochondrial biogenesis in fat cells. Genes Dev 18(16):1970-5. [PubMed: 15289464]  [MGI Ref ID J:91840]

Collin GB; Maddatu TP; Sen S; Naggert JK. 2005. Genetic modifiers interact with Cpefat to affect body weight, adiposity, and hyperglycemia. Physiol Genomics 22(2):182-90. [PubMed: 15870393]  [MGI Ref ID J:100832]

Collins S; Surwit RS. 1996. Pharmacologic manipulation of ob expression in a dietary model of obesity. J Biol Chem 271(16):9437-40. [PubMed: 8621612]  [MGI Ref ID J:33332]

Cool DR; Normant E; Shen F; Chen HC; Pannell L; Zhang Y; Loh YP. 1997. Carboxypeptidase E is a regulated secretory pathway sorting receptor: genetic obliteration leads to endocrine disorders in Cpe(fat) mice. Cell 88(1):73-83. [PubMed: 9019408]  [MGI Ref ID J:38227]

Fricker LD; Berman YL; Leiter EH; Devi LA. 1996. Carboxypeptidase E activity is deficient in mice with the fat mutation. Effect on peptide processing. J Biol Chem 271(48):30619-24. [PubMed: 8940036]  [MGI Ref ID J:36810]

Friis-Hansen L; Lacourse KA; Samuelson LC; Holst JJ. 2001. Attenuated processing of proglucagon and glucagon-like peptide-1 in carboxypeptidase E-deficient mice. J Endocrinol 169(3):595-602. [PubMed: 11375130]  [MGI Ref ID J:88426]

Friis-Hansen L; Rehfeld JF. 2000. Impaired feedback of gastric functions in carboxypeptidase E-deficient mice. Biochem Biophys Res Commun 267(2):638-42. [PubMed: 10631115]  [MGI Ref ID J:60206]

Gomez P; Hallberg L; Greeley GHJr. 1999. Carboxypeptidase E (CPE) deficiency in mice with the fat mutation have reduced stomach function. Proc Soc Exp Biol Med 220(1):52-3. [PubMed: 9893169]  [MGI Ref ID J:52393]

Hosaka M; Watanabe T; Sakai Y; Kato T; Takeuchi T. 2005. Interaction between secretogranin III and carboxypeptidase E facilitates prohormone sorting within secretory granules. J Cell Sci 118(Pt 20):4785-95. [PubMed: 16219686]  [MGI Ref ID J:102191]

Hummel KP; Coleman DL. 1974. fat = fat, Chr UN. Mouse News Lett 50:43.  [MGI Ref ID J:13651]

Irminger JC; Verchere CB; Meyer K; Halban PA. 1997. Proinsulin targeting to the regulated pathway is not impaired in carboxypeptidase E-deficient Cpefat/Cpefat mice. J Biol Chem 272(44):27532-4. [PubMed: 9346885]  [MGI Ref ID J:43715]

Johnston RA; Theman TA; Shore SA. 2006. Augmented responses to ozone in obese carboxypeptidase E-deficient mice. Am J Physiol Regul Integr Comp Physiol 290(1):R126-33. [PubMed: 16002559]  [MGI Ref ID J:104048]

Keightley PD. 1995. Chewing the fat [news] Nat Genet 10(2):125-6. [PubMed: 7663503]  [MGI Ref ID J:24138]

Lacourse KA; Friis-Hansen L; Rehfeld JF; Samuelson LC. 1997. Disturbed progastrin processing in carboxypeptidase E-deficient fat mice. FEBS Lett 416(1):45-50. [PubMed: 9369230]  [MGI Ref ID J:43612]

Lacourse KA; Friis-Hansen L; Samuelson LC; Rehfeld JF. 1998. Altered processing of procholecystokinin in carboxypeptidase E-deficient fat mice: differential synthesis in neurons and endocrine cells. FEBS Lett 436(1):61-6. [PubMed: 9771894]  [MGI Ref ID J:50155]

Leiter EH; Kintner J; Flurkey K; Beamer WG; Naggert JK. 1999. Physiologic and endocrinologic characterization of male sex-biased diabetes in C57BLKS/J mice congenic for the fat mutation at the carboxypeptidease E locus. Endocrine 10(1):57-66. [PubMed: 10403572]  [MGI Ref ID J:54845]

Lim J; Berezniuk I; Che FY; Parikh R; Biswas R; Pan H; Fricker LD. 2006. Altered neuropeptide processing in prefrontal cortex of Cpe (fat/fat) mice: implications for neuropeptide discovery. J Neurochem 96(4):1169-81. [PubMed: 16417576]  [MGI Ref ID J:105999]

Maddatu T; Naggert JK. 1997. Allele-specific PCR assays for the tub and cpefat mutations. Mamm Genome 8(11):857-8. [PubMed: 9337402]  [MGI Ref ID J:44056]

Nillni EA; Xie W; Mulcahy L; Sanchez VC; Wetsel WC. 2002. Deficiencies in pro-thyrotropin-releasing hormone processing and abnormalities in thermoregulation in Cpefat/fat mice. J Biol Chem 277(50):48587-95. [PubMed: 12270926]  [MGI Ref ID J:80698]

Nishina PM; Lowe S; Wang J; Paigen B. 1994. Characterization of plasma lipids in genetically obese mice: the mutants obese, diabetes, fat, tubby, and lethal yellow. Metabolism 43(5):549-53. [PubMed: 8177042]  [MGI Ref ID J:18161]

Nishina PM; Naggert JK; Verstuyft J; Paigen B. 1994. Atherosclerosis in genetically obese mice: the mutants obese, diabetes, fat, tubby, and lethal yellow. Metabolism 43(5):554-8. [PubMed: 8177043]  [MGI Ref ID J:19043]

Rovere C; Viale A; Nahon J; Kitabgi P. 1996. Impaired processing of brain proneurotensin and promelanin-concentrating hormone in obese fat/fat mice. Endocrinology 137(7):2954-8. [PubMed: 8770919]  [MGI Ref ID J:34268]

Shen FS; Aguilera G; Loh YP. 1999. Altered biosynthesis and secretion of pro-opiomelanocortin in the intermediate and anterior pituitary of carboxypeptidase E-deficient, Cpe(fat)/ Cpe(fat)mice. Neuropeptides 33(4):276-80. [PubMed: 10657504]  [MGI Ref ID J:60515]

Shen FS; Loh YP. 1997. Intracellular misrouting and abnormal secretion of adrenocorticotropin and growth hormone in cpefat mice associated with a carboxypeptidase E mutation. Proc Natl Acad Sci U S A 94(10):5314-9. [PubMed: 9144234]  [MGI Ref ID J:40372]

Singh U; Yu Y; Kalinina E; Konno T; Sun T; Ohta H; Wakayama T; Soares MJ; Hemberger M; Fundele RH. 2006. Carboxypeptidase E in the mouse placenta. Differentiation 74(9-10):648-60. [PubMed: 17177860]  [MGI Ref ID J:116679]

Stratigopoulos G; Padilla SL; Leduc CA; Watson E; Hattersley AT; McCarthy MI; Zeltser LM; Chung WK; Leibel RL. 2008. Regulation of Fto/Ftm gene expression in mice and humans. Am J Physiol Regul Integr Comp Physiol 294(4):R1185-96. [PubMed: 18256137]  [MGI Ref ID J:133509]

Udupi V; Gomez P; Song L; Varlamov O; Reed JT; Leiter EH; Fricker LD ; Greeley GH Jr. 1997. Effect of carboxypeptidase E deficiency on progastrin processing and gastrin messenger ribonucleic acid expression in mice with the fat mutation. Endocrinology 138(5):1959-63. [PubMed: 9112393]  [MGI Ref ID J:39758]

Wang F; Tong Q. 2008. Transcription factor PU.1 is expressed in white adipose and inhibits adipocyte differentiation. Am J Physiol Cell Physiol 295(1):C213-20. [PubMed: 18463231]  [MGI Ref ID J:138523]

Wang W; Cain BM; Beinfeld MC. 1998. Adult carboxypeptidase E-deficient fat/fat mice have a near-total depletion of brain CCK 8 accompanied by a massive accumulation of glycine and arginine extended CCK: identification of CCK 8 Gly as the immediate precursor of CCK 8 in rodent brain. Endocrine 9(3):329-32. [PubMed: 10221600]  [MGI Ref ID J:53742]

Wei S; Feng Y; Che FY; Pan H; Mzhavia N; Devi LA; McKinzie AA; Levin N; Richards WG; Fricker LD. 2004. Obesity and diabetes in transgenic mice expressing proSAAS. J Endocrinol 180(3):357-68. [PubMed: 15012590]  [MGI Ref ID J:88683]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           FGB27

Colony Maintenance

Mating System	Heterozygote x Heterozygote         (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 Mouse Mutant Resource collection.

Control Information

	Control
	Heterozygote from the colony
	Wild-type from the colony
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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phone:	207-288-6470
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