These Abca1 knock-out mice exhibit reduced cholesterol and plasma phospholipid levels along with a lack of high density lipoproteins (HDL) . Macrophage ability to engulf apoptotic cells is impaired and lipid rich macrophages and type II pneumocytes accumulate in the lungs.
John D. McNeish, Pfizer Central Research
Mice that are homozygous for the Abca1-null allele are at greater risk of perinatal lethality. Autopsied pups exhibit perivisceral hemorrhaging. Pups that survive beyond birth have no detectable Abca1 gene transcript in the tissues of the liver. Homozygous females suffer from impaired placental development and are unable to produce litters. Both plasma lipids and lipoproteins are markedly reduced. Plasma cholesterol is decreased by approximately 70%. HDL-C and apoAI are decreased by greater than 99%. LDL-C and apoB are also reduced (70 % and 20%, respectively). Other characteristics observed are an increase in intestinal absorption of dietary cholesterol, an impaired ability for macrophages to engulf apoptotic cells and an accumulation of lipid rich macrophages and type II pneumocytes the lungs. These mice display pathophysiologic hallmarks similar to those associated with Tangier disease and provide a tool suitable for use in studies examining membrane lipid homeostasis.
A targeting vector containing a neomycin resistance and herpes simplex virus thymidine kinase genes was used to disrupt exons 17 and 22 of the Abca1 gene. This portion of the gene encodes the the entire N-terminal ATP-binding cassette. The construct was electroporated into DBA/1LacJ-derived 252 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts to generate chimeric animals.
|Allele Name||targeted mutation 1, John D McNeish|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||Abc1-; Abca1-; Abca1-|
|Gene Symbol and Name||Abca1, ATP-binding cassette, sub-family A (ABC1), member 1|
|Strain of Origin||DBA/1LacJ|
|General Note||When used in bone marrow transplant into Ldlrtm1Her homozygous mice, Abca1tm1Jdm Abcg1tm1Dgen homozygous cells accelerate the development of atherosclerosis. (J:130777)|
|Molecular Note||A 5.7 kb genomic fragment containing exons 17-22 was deleted and replaced with a neomycin selection cassette. These sequences correspond to amino acids 788 to 1093 of the encoded protein. RT-PCR analysis on RNA derived from liver demonstrated that no detectable transcript was produced from this allele in homozygous mice.|
|Mutations Made By|| |
John McNeish, Pfizer Central Research
Chimeric animals were mated with DBA/1J mice for an undetermined number of generations. Upon arrival at The Jackson Laboratory, mice were rederived and while held in a live colony, were maintained as heterozygotes by matings with wildtype DBA/1LacJ. Coat color expected from breeding:Dilute Brown
When using the Abc1 KO mouse strain in a publication, please cite the originating article(s) and include JAX stock #003897 in your Materials and Methods section.
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