These Nr1h3 knock-out mice lose their ability to respond normally to dietary cholesterol. This strain may be useful in studies involving fertility, innate immunity, metabolism, and the effects of dietary cholesterol, lipids and carbohydrates
David Mangelsdorf, UT Southwestern Medical Center
Homozygous Nr1h3 (nuclear receptor subfamily 1, group H, member 3) targeted mutation mice lose their ability to respond normally to dietary cholesterol. Mice maintained on cholesterol diets fail to induce transcription of the Cyp7a1 (cytochrome P450, family 7, subfamily a, polypeptide 1) gene, a rate-limiting enzyme in bile acid synthesis, and fail to induce expression of ABCG5 (ATP-binding cassette, sub-family G (WHITE), member 5) and ABCG8 (ATP-binding cassette, sub-family G (WHITE), member 8), ATP-binding cassette transporters that are required for cholesterol secretion into bile. Large amounts of cholesterol rapidly accumulate in the liver leading to impaired hepatic function. Impaired reverse cholesterol transport from peripheral tissues is also observed. The ability to regulate lipids and carbohydrates is also lost. Defects in innate immune responses by activated macrophages have also been described. Males are not infertile, but show a significantly higher number of testicular apoptotic cells than wildtype mice. Testosterone production is significantly lower. It is not known whether genetic background affects the phenotype associated with this mutation.
Exons 3-6, containing the complete DNA-binding domain and majority of the ligand-binding domain, were replaced with a neomycin resistance cassette. The mutation was created in SM1 embryonic stem (ES) cells derived from 129S6/SvEvTac mice. This strain was backcrossed to a 129-derived strain of unknown subline for seven generations by the donating laboratory.
|Allele Name||targeted mutation 1, David J Mangelsdorf|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||LXRalpha (-); Nr1h3-|
|Gene Symbol and Name||Nr1h3, nuclear receptor subfamily 1, group H, member 3|
|Gene Synonym(s)||AU018371; LXR alpha; LXR-a; LXRA; LXRalpha; RLD-1; Unr1; Unr1; expressed sequence AU018371; ubiquitously-expressed nuclear receptor 1|
|Strain of Origin||129S6/SvEvTac|
|Molecular Note||Exons 3-6 encoding the DNA-binding and ligand-binding domains (amino acids 87-327) were replaced with a neomycin resistance gene via homologous recombination. Northern blot and Western blot analysis of liver from homozygous mutant animals verified the absence of mRNA and protein expression.|
|Mutations Made By|| |
David Mangelsdorf, UT Southwestern Medical Center
When maintained as a live colony, homozygotes or heterozygotes may be bred. The donating laboratory reports that breeders between the ages of 2 and 6 months of age show best productivity. They also recommend Teklad Global diets which are free of soybeans for experimental purposes. Soybeans are suspected of masking adrenal and neurodegenerative phenotypes associated with compound mutant strains that incorporate this Nr1h3 mutation (please review published literature). Our "Diet Information" link provides further details of the maintenance feed used at The Jackson Laboratory.
When using the 129-Nr1h3tm1Djm/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #013762 in your Materials and Methods section.
|Heterozygous for Nr1h3<tm1Djm>|
We will fulfill your order by providing at least two carriers for each strain ordered. The total number, sex, and genotypes provided will vary, although typically 8 or more animals are provided. Please check genotypes which will be recovered. While the genotypes of all animals produced will be communicated to you prior to scheduling shipment, the genotypes of animals provided may not reflect the mating scheme and genotypes described in the strain description. Animals are typically ready to ship in 11-14 weeks. If a second recovery is required to produce the minimum number of animals, then delivery time would increase to approximately 25 weeks. If we fail to produce animals of the correct genotype, you will not be charged. We 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.
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