STOCK Cav1^tm1Mls/J

Stock number: 004585
Product name: Cav-1 KO
Research areas: Cardiovascular Research, Developmental Biology Research, Diabetes and Obesity Research, Internal/Organ Research, Metabolism Research, Mouse/Human Gene Homologs, Neurobiology Research

Description

These Caveolin 1 knock-out mice show hyperproliferative and vascular abnormalities. Homozygotes display lipid metabolism and uptake disruption with elevated serum triglycerides and free fatty acid levels, and reduced leptin levels. Young mutant mice exhibit characteristics of Alzheimer's disease. This mutant mouse strain may be useful in studies of vesicular and cholesterol trafficking, signal transduction, neurodegeneration and tumorigenesis.

Note that this allele is also available on a C57BL/6J congenic background (Stock No. 007083).

Detailed description

Mice that are homozygous for the targeted mutation are viable, fertile and do not display any gross physical abnormalities. Mutant mice exhibit exercise intolerance when challenged and are slightly hyperphagic. No gene product (protein) is detected by Western blot analysis in adipose, lung and heart tissues or in cultured mouse embryonic fibroblasts (MEFs). A decrease in the level of co-expressed caveolin-2 protein is immunodetected. At age 4-5 months, mutant mice are often smaller than their wildtype littermates. By one year of age, mutant mice weigh 5 to 7 grams less than wildtype, and are resistant to diet-induced obesity. Progressive adipose pathology results in reduced white adipose tissue with abnormally small adipocytes and enlarged, hyperplastic brown adipose tissue. Homozygotes display lipid metabolism and uptake disruption with elevated serum triglycerides and free fatty acid levels, and reduced leptin levels. Isolated aortic tissue segments have a diminished vasoconstriction response to the alpha-1-adrenergic receptor agonist, phenylephrine, and an enhanced vasorelaxation response to acetylcholine. Histological examination of lung tissue from mutant mice shows thickened alveolar septa, hypercellularity, reduced alveolar spaces and increased density of basement membranes and reticulin fibers. Further immunohistochemical examination of lung tissue shows an increased number of endothelial cells. Mutant derived MEF cells proliferate two times faster and are denser at confluence as indicated by growth curves and cell cycle analysis. Electron microscopy analysis reveals a complete absence of caveolae (plasmalemmal vesicles) in endothelial cells. In vitro studies measuring uptake of fluorescently-labeled albumin and in vivo studies following uptake of gold-conjugated albumin demonstrate caveolar endocytosis impairment.

Young (3-6 month old) mutant mice exhibit multiple characteristics of Alzheimer's disease pathologies including increased amyloid beta and tau deposits, neurodegeneration, astrogliosis and decreased cerebrovascular volume. The neuronal aging found in the hippocampi of young mutant mice resembles that found in aged (> 18 months of age) wild-type mice. The donating investigator noted diminished reproductive performance as the backcross to C57BL/6J background progressed.

Development

A targeting vector containing a neomycin resistance gene was used to disrupt 2.2 Kb of sequence containing exons 1 and 2. The construct was electroporated into WW6 embryonic stem (ES) cells(75% 129/Sv, 20% C57BL/6J, 5% SJL). Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric animals were crossed to C57BL/6J mice for approximately 5 generations. The donating investigator noted diminished reproductive performance as the backcross to C57BL/6J background progressed and backcrossed to a 129S6/SvEv background for 1 generation. The mice are now maintained as homozygotes and are primarily a mix of 129 and C57BL/6, but a minor contribution from the SJL background (contributed from the originating ES cell line) should not be discounted.

Allele

Symbol: Cav1^tm1Mls
Name: targeted mutation 1, Michael P Lisanti
MGI accession ID: MGI:2180364
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Cav1
Marker name: caveolin 1, caveolae protein
Chromosome: 6
Strain of origin: STOCK 129/Sv and C57BL/6J and SJL
Molecular note: A 2.2 kb region of the gene including exons 1 and 2 and part of the promoter region was replaced with a neo resistance cassette via homologous recombination. Absence of gene expression in homozygous mutant animals was verified by Western blot analysis of heart, adipose, and lung tissue, and also of mouse embryonic fibroblasts cultured from E13.5 homozygous mutant embryos.