These Abcb11 knock-out mice exhibit growth retardation and impairment of major hydrophobic bile salts secretion.
Victor Ling, British Columbia Cancer Agency
Mice that are homozygous null for the Abcb11 gene suffer from lowered rates of viability and fertility. No Abcb11 gene product (mRNA or protein) is detected in liver tissue. Homozygotes display growth retardation with body weights being 80% that of wildtype littermates at weaning. Lower body weights persist throughout life. Ultrastructural changes are noted in the hepatic canaliculi (lumen dilation, microvilli loss, and accumulation of biliary material). Hepatocytes exhibit increased numbers of peroxisomes, lysosomes and lipid droplets with a concomitant decrease in stored glycogen. Although average bile flow is not significantly reduced, secretion of major hydrophobic bile salts is clearly impaired. An increase in the secretion of tetra-hydroxylated bile acids, cholesterol and phospholipids is observed. These mice provide a model for studying intrahepatic cholestasis and the mechanisims associated with lipid homeostasis.
A targeting vector containing a neomycin resistance cassette in an antisense orientation with respect to the target gene was used to disrupt the region of the Abcb11 gene encoding amino acids 454-478. Three missense mutations and a premature stop codon at amino acid 454 were also introduced. The construct was electroporated into 129S6/SvEvTac-derived TL-1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting chimeric mice were backcrossed to C57BL/6LJ animals.
|Allele Name||targeted mutation 1, Renxue Wang|
|Allele Type||Targeted (Null/Knockout)|
|Gene Symbol and Name||Abcb11, ATP-binding cassette, sub-family B (MDR/TAP), member 11|
|Strain of Origin||129S6/SvEvTac|
|Molecular Note||The N-terminal ATP-binding domain, corresponding to amino acids 454-478, was deleted and replaced with a neo cassette. The construct introduced three missense mutations and a premature stop codon at position 454. Western analysis showed no detectable protein in homozygous mice.|
|Mutations Made By|| |
Renxue Wang, British Columbia Cancer Agency
This strain originated on a B6;129S6 background and has been backcrossed to C57BL/6J for at least eleven generations (7/01).
When using the spgp- mouse strain in a publication, please cite the originating article(s) and include JAX stock #004125 in your Materials and Methods section.