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 C57BL/6 (see SNP note below) for at least 10 generations by the donating laboratory.
A 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at The Jackson Laboratory Repository. While the 27 markers throughout the genome suggested a C57BL/6 genetic background, at least 3 of 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating. These data suggest the mice sent to The Jackson Laboratory Repository were on a mixed C57BL/6J ; C57BL/6N genetic background.
|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.
The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided,
their gender and genotype will vary. We will fulfill your order by providing at least two pair of mice, at least one animal of
each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders
are needed. Animals typically ship between 10 and 14 weeks from the date of your order. If a second cryorecovery is needed in
order to provide the minimum number of animals, animals will ship within 25 weeks.
The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory 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.
Cryorecovery to establish a Dedicated Supply for greater quantities of mice. Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation.
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