Description

Strain Information

Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse   Donating Investigator Paul Dawson,   Wake Forest University Sch of Medicine

Description
Mice that are homozygous for the targeted mutation are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. Male pups tend to be smaller in size than female pups prior to weaning. No gene product (mRNA or protein) is detected by Northern or Western blot analysis of the distal small intestine. Ileal brush border membrane vesicles isolated from homozygotes do not exhibit sodium ion dependent taurocholate uptake, indicating a loss of sodium bile acid cotransporter activity. Total plasma cholesterol levels are slightly higher than normal. Total bile acid pool size is reduced approximately 80% in homozygous mutants, although intestinal lipid absorption is reduced by only about 10%. Bile acid functional turnover rate (daily fecal bile acid excretion/pool size) is elevated 150 fold in male mutants and 75 fold in female mutants. Fecal bile acid excretion is increased 24 fold in male mutants and 11 fold in female mutants. Bile acid composition is abnormal. Fecal lipid excretion of total fat, fatty acid and neutral sterols is increased approximately 4 fold. Cholesterol absorption in the intestine is reduced by 26% in male mutants and 15% in female mutants. Cholesterol 7 alpha hydroxylase activity is increased by 2.7 fold in males and 5.2 fold in females homozygous for the mutant allele. Hepatic bile acid synthesis is increased and total hepatic cholesterol and cholesteryl ester levels are reduced. This mutant mouse strain may be useful in studies of cholesterol, lipoprotein and bile acid metabolism, and primary bile acid malabsorption.

Development
A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was used to disrupt exon 3 and the splice acceptor site of exon 4. The construct was electroporated into 129P2/OlaHsd derived E14TG2a embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting chimeric animals were crossed to 129S6/SvEvTac mice. Heterozygotes were bred to generate homozygotes.

Control Information

	Control
	Wild-type from the colony
	002448 129S1/SvImJ
		Appropriate controls depend on the nature of the experiment. Wildtype mice from the colony or 129S1/SvImJ mice (Stock No. 002448) may be included among the controls considered.
Considerations for Choosing Controls

Additional Web Information

Genetic Quality Control Annual Report

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Slc10a2^tm1Pda/Slc10a2^tm1Pda

        either: (involves: 129P2/OlaHsd * 129S6/SvEv) or (involves: 129P2/OlaHsd * C57BL/6J)

• digestive/alimentary phenotype
• abnormal nutrient absorption (MGI Ref ID J:85312)
  • fecal bile acid excretion increased 24X in males and 11X in females
  • decrease in intestinal absorption of lipid from 98% to 95% in females and 93% in males
  • 26% reduction in cholesterol absorption in males and 15% reduction in females
• steatorrhea (MGI Ref ID J:85312)
  • 4X increase in total fat, fatty acid, and neutral sterol excretion
  • amount of fat excreted is small however
• growth/size phenotype
• decreased body weight (MGI Ref ID J:85312)
  • small growth deficit in males but not females prior to weaning
  • 20% decrease in body weight was transitory
• homeostasis/metabolism phenotype
• abnormal bile salt homeostasis (MGI Ref ID J:85312)
  • total bile acid pool decreased 83% in males and 80% in females
• abnormal bile salt level (MGI Ref ID J:85312)
  • bile acid pool composition is altered, taurocholate predominates
• abnormal lipid homeostasis (MGI Ref ID J:85312)
• increased circulating cholesterol level (MGI Ref ID J:85312)
  • small but signifacant increase seen
• liver/biliary system phenotype
• abnormal bile composition (MGI Ref ID J:85312)
  • bile acid pool composition is altered, taurocholate predominates
• abnormal liver physiology (MGI Ref ID J:85312)
  • huge elevation in bile acid fractional turnover rate, 150% in males and 75% in females
  • cholesteryl ester levels in liver are significantly lower

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

Slc10a2^tm1Pda/Slc10a2^tm1Pda

        either: B6.129P2-Slc10a2^tm1Pda or (involves: 129P2/OlaHsd * C57BL/6J)

• homeostasis/metabolism phenotype
• abnormal bile salt homeostasis (MGI Ref ID J:132778)
  • in everted gut sac experiments, mucosal-to-serosal transport of taurocholate is reduced, indicating impaired intestinal bile acid transport

View Research Applications

Research Applications

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

Slc10a2^tm1Pda related

Cardiovascular Research
Hypercholesterolemia

Metabolism Research
Lipid Metabolism

Genes & Alleles

Gene & Allele Information

Allele Symbol		Slc10a2tm1Pda
Allele Name		targeted mutation 1, Paul A Dawson
Allele Type		Targeted (knock-out)
Common Name(s)		Asbt-; Slc10a2-/-;
Mutation Made By		Paul Dawson,   Wake Forest University Sch of Medicine
Strain of Origin		129P2/OlaHsd
ES Cell Line Name		E14TG2a
ES Cell Line Strain		129P2/OlaHsd
Gene Symbol and Name		Slc10a2, solute carrier family 10, member 2
Chromosome		8
Gene Common Name(s)		ASBT; ISBAT; ISBT; NTCP2;
Molecular Note		A region of the gene extending from intron 2 through to the splice acceptor site of exon 4 was replaced with a neomycin resistance cassette. Absence of gene products was confirmed by Northern blots and by immunoblots. [MGI Ref ID J:85312]

Genotyping

Genotyping Information

This strain will not have a genotyping protocol or one is not currently available.

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Dawson PA; Haywood J; Craddock AL; Wilson M; Tietjen M; Kluckman K; Maeda N; Parks JS. 2003. Targeted deletion of the ileal bile acid transporter eliminates enterohepatic cycling of bile acids in mice. J Biol Chem 278(36):33920-7. [PubMed: 12819193]  [MGI Ref ID J:85312]

Additional References

Slc10a2^tm1Pda related

Dawson PA; Hubbert M; Haywood J; Craddock AL; Zerangue N; Christian WV; Ballatori N. 2005. The heteromeric organic solute transporter alpha-beta, Ostalpha-Ostbeta, is an ileal basolateral bile acid transporter. J Biol Chem 280(8):6960-8. [PubMed: 15563450]  [MGI Ref ID J:106032]

Jung D; Inagaki T; Gerard RD; Dawson PA; Kliewer SA; Mangelsdorf DJ; Moschetta A. 2007. FXR agonists and FGF15 reduce fecal bile acid excretion in a mouse model of bile acid malabsorption. J Lipid Res 48(12):2693-700. [PubMed: 17823457]  [MGI Ref ID J:129925]

Rao A; Haywood J; Craddock AL; Belinsky MG; Kruh GD; Dawson PA. 2008. The organic solute transporter alpha-beta, Ostalpha-Ostbeta, is essential for intestinal bile acid transport and homeostasis. Proc Natl Acad Sci U S A 105(10):3891-6. [PubMed: 18292224]  [MGI Ref ID J:132778]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	This strain is maintained as a heterozygote. Male pups tend to be smaller in size than female pups prior to weaning.
Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information.

Supply Notes

Cryopreserved Embryos This strain is also available as cryopreserved embryos from our Repository. Orders for cryopreserved embryos are supplied subject to a signed agreement that must be returned to the Customer Service Department after order placement. Experienced technicians at The Jackson Laboratory have recovered frozen embryos of this strain successfully. We will provide you enough embryos to perform two embryo transfers. The Jackson Laboratory does not guarantee successful recovery at your facility. For complete information on purchasing embryos from our repository, please visit our Cryopreserved Embryos web page. Cryorecovery - Standard. The recovery process begins when a signed agreement form is returned to the Customer Service Department after order placement. Although results vary by strain, at least two males and two females (two pairs) will be provided, typically within 15 weeks of our receipt of the signed agreement form. If the first recovery attempt is unsuccessful or only one pair is recovered, a second recovery will be done, extending the delivery time to approximately 25 weeks. At least one member of each pair will be of known genotype and will carry the mutation if it is a mutant strain. Please note that pairs may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation of the strain. Mating schemes are sometimes modified for successful cryopreservation. Price represents a repository maintenance fee, which includes the cost of recovery of the strain from the cryopreservation resource and the periodic replacement of the frozen embryos used for recovery. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. One to two pairs will be recovered to establish a Dedicated Supply of mice. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 or 1-207-288-5845. This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	Wild-type from the colony
	002448 129S1/SvImJ
		Appropriate controls depend on the nature of the experiment. Wildtype mice from the colony or 129S1/SvImJ mice (Stock No. 002448) may be included among the controls considered.
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

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.”

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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.