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

Former Names B6.129X1(FVB)-Hnf4tm1.1Gonz/J    (Changed: 05-JAN-05 ) Type Congenic; Mutant Strain; 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. Frank Gonzalez,   National Institutes of Health

Description
Mice homozygous for this allele are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. Similarly oriented loxP sites are positioned in introns 3 and 5 of the targeted gene. When used in conjunction with a Cre recombinase-expressing strain, this mouse can be used to generate tissue-specific mutants. Cre-directed recombination results in the deletion of the loxP-flanked sequence causing a splicing event between exons 3 and exon 6. A frame shift occurs generating a premature stop codon. A putative truncated protein may be translated, but such a protein would lack the A and T box motifs necessary for high-affinity binding to DNA. This mouse mutant may be useful in studies related to lipid homeostasis.

When bred to a strain expressing Cre recombinase in pancreatic beta cells (see Stock No. 003573 for example), this mutant mouse strain may be useful in studies of insulin secretion.

Development
A loxP-flanked targeting vector containing a neomycin resistance gene was utilized in the construction of this mutant. The neomycin selection cassette was inserted downstream of exon 5 of the targeted gene. Another loxP site was inserted upstream of exon 4. The construct was electroporated into 129X1/SvJ-derived RW4 embryonic stem (ES) cells and correctly targeted ES cells were injected into C57BL/6 blastocysts. Chimeric animals were bred to C57BL/6 mice. To delete the loxP-flanked neomycin resistance cassette, heterozygous mice were mated to FVB animals bearing an EIIa-Cre transgene. Mice with loxP sites flanking exons 4 and 5 were obtained and mated to C57BL/6 mice for five generations before being made homozygous.

Control Information

	Control
	000664 C57BL/6J	(approximate)
Considerations for Choosing Controls

Additional Web Information

Introduction to Cre-lox technology

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Maturity-Onset Diabetes of the Young, Type 1; MODY1

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Diabetes Mellitus, Noninsulin-Dependent; NIDDM   (HNF4A)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

The following phenotype relates to a compound genotype created using this strain.
Contact JAX^® Services jaxservices@jax.org for customized breeding options.

Hnf4a^tm1.1Gonz/Hnf4a^tm1.1Gonz Tg(Ins2-cre)25Mgn/0

        involves: 129X1/SvJ * C57BL/6 * DBA   (conditional)

• homeostasis/metabolism phenotype
• decreased circulating insulin level
  • at 10 weeks of age, females exhibit poor initial response of insulin secretion after receiving a glucose load; at 24 weeks, both males and females exhibit an impaired insulin response   (MGI Ref ID J:108652)
  • insulin secretion in response to high glucose levels is reduced in perfused islets from knockouts   (MGI Ref ID J:108652)
• impaired glucose tolerance
  • glucose level at 12, 30, 60 and 120 minutes after administration of a glucose load are higher in females at 10 weeks compared to controls; at 24 weeks both males and females exhibit glucose intolerance   (MGI Ref ID J:108652)
• nervous system phenotype
• abnormal channel response
  • K_ATP activity is reduced in knockouts; decreased response leads to impaired insulin secretion   (MGI Ref ID J:108652)

View Research Applications

Research Applications

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

Research Tools
Cre-lox System
      loxP-flanked Sequences

Hnf4a^tm1.1Gonz related

Research Tools
Metabolism Research

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Hnf4atm1.1Gonz
Allele Name		targeted mutation 1.1, Frank J Gonzalez
Allele Type		Targeted (Floxed/Frt)
Common Name(s)		HNF4-alphafl; HNF4-alphaflox; HNF4alpha-flox; HNF4alphaflox; Hnf4aloxP; hnf4fl;
Strain of Origin		129X1/SvJ
ES Cell Line Name		RW-4
ES Cell Line Strain		129X1/SvJ
Gene Symbol and Name		Hnf4a, hepatic nuclear factor 4, alpha
Chromosome		2
Gene Common Name(s)		HNF-4; HNF4; HNF4 alpha; HNF4a7; HNF4a8; HNF4a9; HNF4alpha; Hnf4; MODY; MODY1; NR2A1; NR2A21; Nuclear receptor 2A1; TCF; TCF14; Tcf14; Tcf4; hepatic nuclear factor 4; transcription factor 14;
Molecular Note		This allele was generated by breeding mice carrying Hnf4tm1Gonz with transgenic mice expressing cre recombinase via the EIIa promoter. Expression of cre resulted in the excision of the floxed neomycin cassette, leaving a floxed region containing exons 4 and 5. Hnf4tm1.2Gonz was simultaneously generated by the same strategy. [MGI Ref ID J:67396]

Genotyping

Genotyping Information

Genotyping Protocols

Hnf4a^tm1.1Gonz, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Hayhurst GP; Lee YH; Lambert G; Ward JM; Gonzalez FJ. 2001. Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol 21(4):1393-403. [PubMed: 11158324]  [MGI Ref ID J:67396]

Additional References

Hnf4a^tm1.1Gonz related

Babeu JP; Darsigny M; Lussier CR; Boudreau F. 2009. Hepatocyte nuclear factor 4alpha contributes to an intestinal epithelial phenotype in vitro and plays a partial role in mouse intestinal epithelium differentiation. Am J Physiol Gastrointest Liver Physiol 297(1):G124-34. [PubMed: 19389805]  [MGI Ref ID J:151206]

Beaudry JB; Pierreux CE; Hayhurst GP; Plumb-Rudewiez N; Weiss MC; Rousseau GG; Lemaigre FP. 2006. Threshold levels of hepatocyte nuclear factor 6 (HNF-6) acting in synergy with HNF-4 and PGC-1alpha are required for time-specific gene expression during liver development. Mol Cell Biol 26(16):6037-46. [PubMed: 16880515]  [MGI Ref ID J:111407]

Bonzo JA; Ferry CH; Matsubara T; Kim JH; Gonzalez FJ. 2012. Suppression of hepatocyte proliferation by hepatocyte nuclear factor 4alpha in adult mice. J Biol Chem 287(10):7345-56. [PubMed: 22241473]  [MGI Ref ID J:182767]

Cattin AL; Le Beyec J; Barreau F; Saint-Just S; Houllier A; Gonzalez FJ; Robine S; Pincon-Raymond M; Cardot P; Lacasa M; Ribeiro A. 2009. Hepatocyte nuclear factor 4alpha, a key factor for homeostasis, cell architecture, and barrier function of the adult intestinal epithelium. Mol Cell Biol 29(23):6294-308. [PubMed: 19805521]  [MGI Ref ID J:154985]

Corchero J; Granvil CP; Akiyama TE; Hayhurst GP; Pimprale S; Feigenbaum L; Idle JR; Gonzalez FJ. 2001. The CYP2D6 humanized mouse: effect of the human CYP2D6 transgene and HNF4alpha on the disposition of debrisoquine in the mouse. Mol Pharmacol 60(6):1260-7. [PubMed: 11723233]  [MGI Ref ID J:104020]

Darsigny M; Babeu JP; Dupuis AA; Furth EE; Seidman EG; Levy E; Verdu EF; Gendron FP; Boudreau F. 2009. Loss of hepatocyte-nuclear-factor-4alpha affects colonic ion transport and causes chronic inflammation resembling inflammatory bowel disease in mice. PLoS One 4(10):e7609. [PubMed: 19898610]  [MGI Ref ID J:158289]

Darsigny M; Babeu JP; Seidman EG; Gendron FP; Levy E; Carrier J; Perreault N; Boudreau F. 2010. Hepatocyte nuclear factor-4alpha promotes gut neoplasia in mice and protects against the production of reactive oxygen species. Cancer Res 70(22):9423-33. [PubMed: 21062980]  [MGI Ref ID J:166855]

Ding X; Lichti K; Kim I; Gonzalez FJ; Staudinger JL. 2006. Regulation of constitutive androstane receptor and its target genes by fasting, cAMP, hepatocyte nuclear factor alpha, and the coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha. J Biol Chem 281(36):26540-51. [PubMed: 16825189]  [MGI Ref ID J:117299]

Frochot V; Alqub M; Cattin AL; Carriere V; Houllier A; Baraille F; Barbot L; Saint-Just S; Ribeiro A; Lacasa M; Cardot P; Chambaz J; Rousset M; Lacorte JM. 2012. The transcription factor HNF-4alpha: a key factor of the intestinal uptake of fatty acids in mouse. Am J Physiol Gastrointest Liver Physiol 302(11):G1253-63. [PubMed: 22461026]  [MGI Ref ID J:191159]

Hayhurst GP; Strick-Marchand H; Mulet C; Richard AF; Morosan S; Kremsdorf D; Weiss MC. 2008. Morphogenetic competence of HNF4alpha-deficient mouse hepatic cells. J Hepatol 49(3):384-95. [PubMed: 18617288]  [MGI Ref ID J:138863]

Holloway MG; Laz EV; Waxman DJ. 2006. Codependence of growth hormone-responsive, sexually dimorphic hepatic gene expression on signal transducer and activator of transcription 5b and hepatic nuclear factor 4alpha. Mol Endocrinol 20(3):647-60. [PubMed: 16239260]  [MGI Ref ID J:105869]

Inoue Y; Hayhurst GP; Inoue J; Mori M; Gonzalez FJ. 2002. Defective ureagenesis in mice carrying a liver-specific disruption of hepatocyte nuclear factor 4alpha (HNF4alpha ). HNF4alpha regulates ornithine transcarbamylase in vivo. J Biol Chem 277(28):25257-65. [PubMed: 11994307]  [MGI Ref ID J:77808]

Inoue Y; Yu AM; Yim SH; Ma X; Krausz KW; Inoue J; Xiang CC; Brownstein MJ; Eggertsen G; Bjorkhem I; Gonzalez FJ. 2006. Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4alpha. J Lipid Res 47(1):215-27. [PubMed: 16264197]  [MGI Ref ID J:106030]

Laz EV; Holloway MG; Chen CS; Waxman DJ. 2007. Characterization of three growth hormone-responsive transcription factors preferentially expressed in adult female liver. Endocrinology 148(7):3327-37. [PubMed: 17412818]  [MGI Ref ID J:129617]

Martinez-Jimenez CP; Kyrmizi I; Cardot P; Gonzalez FJ; Talianidis I. 2010. Hepatocyte nuclear factor 4alpha coordinates a transcription factor network regulating hepatic fatty acid metabolism. Mol Cell Biol 30(3):565-77. [PubMed: 19933841]  [MGI Ref ID J:156389]

Miura A; Yamagata K; Kakei M; Hatakeyama H; Takahashi N; Fukui K; Nammo T; Yoneda K; Inoue Y; Sladek FM; Magnuson MA; Kasai H; Miyagawa J; Gonzalez FJ; Shimomura I. 2006. Hepatocyte nuclear factor-4alpha is essential for glucose-stimulated insulin secretion by pancreatic beta-cells. J Biol Chem 281(8):5246-57. [PubMed: 16377800]  [MGI Ref ID J:108652]

Ohguchi H; Tanaka T; Uchida A; Magoori K; Kudo H; Kim I; Daigo K; Sakakibara I; Okamura M; Harigae H; Sasaki T; Osborne TF; Gonzalez FJ; Hamakubo T; Kodama T; Sakai J. 2008. Hepatocyte nuclear factor 4alpha contributes to thyroid hormone homeostasis by cooperatively regulating the type 1 iodothyronine deiodinase gene with GATA4 and Kruppel-like transcription factor 9. Mol Cell Biol 28(12):3917-31. [PubMed: 18426912]  [MGI Ref ID J:137297]

Pearson ER; Boj SF; Steele AM; Barrett T; Stals K; Shield JP; Ellard S; Ferrer J; Hattersley AT. 2007. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med 4(4):e118. [PubMed: 17407387]  [MGI Ref ID J:134163]

Wiwi CA; Gupte M; Waxman DJ. 2004. Sexually dimorphic P450 gene expression in liver-specific hepatocyte nuclear factor 4alpha-deficient mice. Mol Endocrinol 18(8):1975-87. [PubMed: 15155787]  [MGI Ref ID J:119837]

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	The Hnf4 gene is located on Chromosome 2 positioned near to the nonagouti locus. This segment of the genome is derived from the donor strain (129X1). Most progeny are agouti. Expected Coat color is Agouti and Agouti with pink eye dilution.
Diet Information	LabDiet® 5K52/5K67

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

General Supply Notes

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

Control Information

	Control
	000664 C57BL/6J	(approximate)
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

Payment Terms and Conditions

Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

See Terms of Use tab for General Terms and Conditions

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.

---

Ordering Information
JAX^® Mice
Surgical and Preconditioning Services
JAX^® Services
Customer Services and Support
Tel: 1-800-422-6423 or 1-207-288-5845
Fax: 1-207-288-6150
Technical Support Email Form

Terms of Use

Terms of Use

General Terms and Conditions

Contact information

General inquiries regarding Terms of Use

Contracts Administration

phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice, Products & Services Conditions of Use

"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.

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, JACKSON will, at its option, provide credit or replacement for the mice or product received or the services provided.

No Liability

In no event shall JACKSON, 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 JACKSON, its agents or employees. Unless prohibited by law, in purchasing or receiving MICE, PRODUCTS or services from JACKSON, purchaser or recipient, or any party claiming by or through them, expressly releases and discharges JACKSON from all such causes of action or damages, and further agrees to defend and indemnify JACKSON from any costs or damages arising out of any third party claims.

MICE and PRODUCTS are to be used in a safe manner and in accordance with all applicable governmental rules and regulations.

The foregoing represents the General Terms and Conditions applicable to JACKSON’s MICE, PRODUCTS or services. In addition, special terms and conditions of sale of certain MICE, PRODUCTS or services may be set forth separately in JACKSON 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 JACKSON, 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 JACKSON, 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 or services by JACKSON.