129-Nr1h3^tm1Djm/J

Stock number: 013762
Research areas: Cardiovascular Research, Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Metabolism Research, Reproductive Biology Research

Description

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

Detailed description

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.

Development

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

Symbol: Nr1h3^tm1Djm
Name: targeted mutation 1, David J Mangelsdorf
MGI accession ID: MGI:2181380
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Nr1h3
Marker name: nuclear receptor subfamily 1, group H, member 3
Chromosome: 2
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.