Description

Strain Information

Type Congenic; Mutant Strain; Transgenic; Additional information on Genetically Engineered Mutant Mice. Mating System Noncarrier x Hemizygote         (Female x Male) Species laboratory mouse Generation N10+F0 (16-SEP-08)   Donating Investigator Ajay Shah,   King's College London

Description
Mice hemizygous for the hIGFBP-1 transgene are viable and fertile with no reported gross morphological or developmental changes. The hIGFBP-1 transgene encompasses the entire human IGFBP-1 structural gene and its regulatory sequences, allowing transgene expression of IGFBP-1 to remain responsive to normal hormonal regulation. Transgenic mice overexpress hIGFBP-1, with hIGFBP-1 mRNA expression in a tissue-specific fashion more similar to the human pattern than the murine pattern. Fasting transgenic mice have elevated total serum IGFBP-1 levels that fluctuate according to nutritional status (as they do in humans), and exhibit postprandial hyperinsulinemia with preservation of normal glucocompetence and insulin sensitivity. Transgenic mice also have significantly greater hyperinsulinemic response to glucose challenge and cardiovascular abnormalities in response to carbohydrate load and vasoconstrictors. Transgenic mice exhibit fasting hyperglycemia and hyperinsulinemia and glucose intolerance in later life. The phenotype of hIGFBP-1 overexpressing mice may vary between male and female mice. These hIGFBP-1 transgenic mice may be useful in studying metabolic and vascular homeostasis, diabetes, and the role of insulin-like growth factor binding protein in placentation and preeclampsia.

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. As these mice were originally characterized on both C57BL/CBA mixed and CBA congenic backgrounds, 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
The hIGFBP-1 transgene (isolated from a human cosmid clone) contains the entire structural IGFBP1 gene and all the cis acting sequences necessary to direct appropriate tissue-specific and regulated gene expression. This 35 kb transgene was microinjected into the male pronucleus of C57BL/CBA fertilized oocytes. Founder mice (line c1:2-2) were bred to CBA/Ca and the transgene copy number was found to be between 8 and 20. After this, hIGFBP-1 transgenic mice were backcrossed to C57BL/6J mice for at least 9 generations prior to arrival at The Jackson Laboratory. Upon arrival, mice were additionally backcrossed to C57BL/6J for at least one generation.

Control Information

	Control
	Noncarrier
	000664 C57BL/6J
Considerations for Choosing Controls

Additional Web Information

Congenic Nomenclature

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.

Tg(IGFBP1)2Miel/0

        involves: C57BL * CBA

• growth/size phenotype
• decreased body weight (MGI Ref ID J:128964)
  • at ~3 weeks, mice are ~10% lighter than wild-type littermates, but by 8 weeks of age, this difference is no longer statistically significant
• homeostasis/metabolism phenotype
• *normal* homeostasis/metabolism phenotype (MGI Ref ID J:128964)
  • fasting blood glucose and insulin levels at 16-20 weeks are similar to wild-type animals
  • intraperitoneal glucose and insulin tolerance tests do not differ from wild-type results
  • fasting plasma lipoprotein, triglyceride, and free fatty acid levels do not differ from wild-type
• abnormal glucose homeostasis (MGI Ref ID J:128964)
  • hypoglycemic response to exogenous IGF-1 is attenuated in transgenic animals relative to controls
  • blood glucose levels in transgenic mice are higher at all time points after glucose challenge but difference is significant only at 60 and 120 minutes
  • initial increase in blood glucose in response to IGF-1 observed in wild-type males is abolished in transgenic males
  • glucocompetence deteriorates with age
• impaired glucose tolerance (MGI Ref ID J:128964)
  • 16-20 week-old mice show significant impairment in glucose tolerance compared to wild-type
  • fasted mice challenged with IP injection of glucose show insulin levels that are 2.5 fold higher in transgenic males than control males at 30 minutes post-injection; insulin levels are 37% higher at 30 minutes in transgenic females relative to wild-type
  • glucose/insulin rario is lower in transgenic males after glucose challenge relative to wild-type; males have higher 30-minute glucose and insulin levels compared with females
  • ability to dispose of intraperitoneally administered glucose load is markedly impaired in aged mice compared to sex- and age-matched controls
• increased circulating glucose level (MGI Ref ID J:128964)
  • at 40-44 weeks, males have increased fasting blood glucose levels
• increased circulating insulin level (MGI Ref ID J:128964)
  • at 40-44 weeks, males have increased fasting insulin levels; fasting human IGFBP-1 levels are reduced reflecting relative hyperinsulinemia
  • mice exhibit a significantly greater hyperinsulinemic response to a glucose challenge than wild-type mice
• cardiovascular system phenotype
• decreased systolic blood pressure (MGI Ref ID J:84652)
  • norm systolic blood pressure in fasted mutants does not differ from wild-type mice
  • mutants experience a significant fall in pressure 30 minutes after intraperitoneal glucose challenge, but wild-type do not show this
• decreased vasoconstriction (MGI Ref ID J:84652)
  • magnitude of vasoconstriction response of aortic rings in transgenic mice to increasing concentrations of phenylephrine is significantly attenuated compared to wild-type mice (E_max1.13 g/mg in transgenics compared to 1.55 g/mg in wild-type)
  • vasoconstriction in response to potassium chloride is reduced compared to wild-type
  • when pre-constricted rings are incubated for 30 minutes with a nitric oxide inhibitor L-NMMA, rings from transgenic mice display a greater increment in tension than rings from wild-type mice
  • norm relaxation of pre-constricted rings in response to vasodilators (acetycholine or sodium nitroprusside) is similar in both genotypes

Tg(IGFBP1)2Miel/0

        CBACa.Cg-Tg(IGFBP1)2Miel

• lethality-prenatal/perinatal
• prenatal lethality (MGI Ref ID J:78353)
  • fetal death rate in litters of transgenic dams is 12%, compared to no lethality in litters from wild-type dams
• embryogenesis phenotype
• abnormal maternal decidual layer morphology (MGI Ref ID J:78353)
  • decidual component of placentas in wild-type dams is greater than that of transgenic dams
• abnormal placenta junctional zone morphology (MGI Ref ID J:78353)
  • junctional zone is larger in placentae from wild-type females compared to transgenic mice
• abnormal spongiotrophoblast layer morphology (MGI Ref ID J:78353)
  • ratio of spongiotrophoblasts to glycogen cells is higher in transgenic females
• abnormal placenta labyrinth morphology (MGI Ref ID J:78353)
  • labyrinthine zone is grossly enlarged in transgenic females, occupying 80% of cross-sectional area of placenta in transgenic females, compared to ~50% of area in wild-type females
• embryonic growth retardation (MGI Ref ID J:78353)
  • at E11.5, embryonic growth restriction is observed in transgenic dams
  • at E14.5 and 17.5 fetal growth is similar in transgenic and wild-type dams
• increased placenta weight (MGI Ref ID J:78353)
  • transgenic dams have higher mean placental weights throughout gestation
• reduced embryo size (MGI Ref ID J:78353)
  • at E11.5, fetuses exhibit a ~10% reduction in weight compared to wild-type fetuses; difference is less at E14.5 and by E17.5, mutants and wild-type have very similar growth characteristics
• growth/size phenotype
• embryonic growth retardation (MGI Ref ID J:78353)
  • at E11.5, embryonic growth restriction is observed in transgenic dams
  • at E14.5 and 17.5 fetal growth is similar in transgenic and wild-type dams
• reduced embryo size (MGI Ref ID J:78353)
  • at E11.5, fetuses exhibit a ~10% reduction in weight compared to wild-type fetuses; difference is less at E14.5 and by E17.5, mutants and wild-type have very similar growth characteristics
• reproductive system phenotype
• abnormal decidualization (MGI Ref ID J:78353)

View Research Applications

Research Applications

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

Cardiovascular Research
Other

Diabetes and Obesity Research
Hyperglycemia (adult onset)
Hyperinsulinemia
Insulin Receptors and Growth Factors
Obesity With Diabetes
Obesity Without Diabetes
Type 2 Diabetes (NIDDM)

Metabolism Research

Research Tools
Cardiovascular Research
Developmental Biology Research
Diabetes and Obesity Research
Metabolism Research

Genes & Alleles

Gene & Allele Information

Allele Symbol		Tg(IGFBP1)2Miel
Allele Name		transgene insertion 2, John Miell
Allele Type		Transgenic (random, expressed)
Common Name(s)		c1:2-2; hIGFBP-1 (line c1:2-2);
Mutation Made By		John Miell,   University Hospital Lewisham
Strain of Origin		C57BL and CBA
Expressed Gene		IGFBP1, insulin-like growth factor binding protein 1, human
Promoter		IGFBP1, insulin-like growth factor binding protein 1, human
Molecular Note		The hIGFBP-1 transgene (isolated from a human cosmid clone) contains the entire structural IGFBP1 gene and all the cis acting sequences necessary to direct appropriate tissue-specific and regulated gene expression. Founder mice (line c1:2-2) were bred toCBA/Ca and the transgene copy number was found to be between 8 and 20. [MGI Ref ID J:128964]

Genotyping

Genotyping Information

Genotyping Protocols

Tg(IGFBP1)2Miel, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Crossey PA; Jones JS; Miell JP. 2000. Dysregulation of the insulin/IGF binding protein-1 axis in transgenic mice is associated with hyperinsulinemia and glucose intolerance. Diabetes 49(3):457-65. [PubMed: 10868969]  [MGI Ref ID J:128964]

Crossey PA; Pillai CC; Miell JP. 2002. Altered placental development and intrauterine growth restriction in IGF binding protein-1 transgenic mice. J Clin Invest 110(3):411-8. [PubMed: 12163461]  [MGI Ref ID J:78353]

Wheatcroft SB; Kearney MT; Shah AM; Grieve DJ; Williams IL; Miell JP; Crossey PA. 2003. Vascular endothelial function and blood pressure homeostasis in mice overexpressing IGF binding protein-1. Diabetes 52(8):2075-82. [PubMed: 12882925]  [MGI Ref ID J:84652]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX11

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, carrier mice may be bred to wildtype or C57BL/6J inbred mice.
Mating System	Noncarrier x Hemizygote         (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
	Noncarrier
	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.

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Tel: 800.422.6423 or 207.288.5845
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Terms of Use

Terms of Use

General Terms and Conditions

Contact information

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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.”

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.

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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.

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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.