These Nr1h4 knock-out mice exhibit pro-atherogenic serum lipoprotein profile characterized by elevated levels of serum and hepatic cholesterol and triglycerides.
Frank J Gonzalez, National Institutes of Health (NIH/NCI)
Mice that are homozygous for the targeted Nr1h4 allele are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. No Nr1h4 protein product is detected in liver tissue although an aberrant transcript appears to be generated. Homozygous mice display a proatherogenic serum lipoprotein profile characterized by elevated levels of serum and hepatic cholesterol and triglycerides. Serum bile acids are also elevated. When fed a diet supplemented with 1% cholic acid, severe wasting, hypothermia and increased mortality is observed. Wildtype mice fed a similar diet display no ill effects. Levels of fecal bile excretion are reduced in homozygotes. This mutant mouse strain represents a model that may be useful in studies related to bile acid and lipid homeostasis.
A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was used to disrupt the exon encoding the ligand-binding domain (nts 1238-1779). A loxP site was placed 5' of the targeted exon. The neomycin resistance and thymidine kinase genes were flanked by loxP sites and placed 3' of the targeted exon. The construct was electroporated into 129X1/SvJ-derived embryonic stem (ES) cells from Genome Systems Inc. (St. Louis, MO). Correctly targeted ES cells were injected into C57BL/6N blastocysts. The resulting chimeric animals were crossed to female C57BL/6N mice. Progeny animals were mated with heterozygous transgenic mice expressing Cre recombinase (EIIA promoter) on a pure FVB background. Offspring bearing the recombined Nr1h4 allele, but not the Cre transgene were obtained.
|Allele Name||targeted mutation 1, Frank Gonzalez|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||FXR/BAR -; FXR-; Fxrtm1Gonz; FXRalpha-|
|Gene Symbol and Name||Nr1h4, nuclear receptor subfamily 1, group H, member 4|
|Strain of Origin||129X1/SvJ|
|General Note||The ES cell line was not specified, but was purchased from Genome Systems (St. Louis, MO). (Note added 7/26/01: Genome Systems was bought by Incyte.)|
|Molecular Note||Mice with a targeted deletion of the last exon encoding the ligand binding domain and all of the 3' untranslated region were produced as follows: A loxP site was inserted in the intron 5' to the last exon and a loxP-flanked neomycin cassette was inserted 3' to the last exon. After production of chimeric founder mice, F1 mice were mated to Tg(EIIa-Cre)1Lmgd mice to produce offspring that carried a recombined deletion of the last exon and neomycin cassette. No Nr1h4 protein product is detected in liver tissue from these null mice although an aberrant transcript appears to be generated.|
|Mutations Made By|| |
Frank Gonzalez, National Institutes of Health (NIH/NCI)
This strain originated on a B6;129X1 background, was crossed to a pure FVB mouse once (a Cre strain) and then crossed to C57BL/6N twice before being made homozygous. Expected coat color is: Black
When using the FXR/BAR- mouse strain in a publication, please cite the originating article(s) and include JAX stock #004144 in your Materials and Methods section.