B6.129S4-Pparg^tm1Rev/J

Stock number: 006142
Product name: PPARgamma KO
Research areas: Cardiovascular Research, Developmental Biology Research, Diabetes and Obesity Research, Research Tools

Description

PPAR gamma deficiency in these knock-out mice interferes with terminal differentiation of the trophoblast and placental vascularization, leading to myocardial thinning and death by E10.0. A lacZ reporter in these mice recapitulates the endogenous Pparg expression pattern.

Detailed description

All mice homozygous for this targeted mutation die after gestational day 9.5 from severe placental defects and myocardial thinning. Heterozygotes are viable and fertile. White adipose tissue from heterozygous mice display approximately half the mRNA expression compared to wildtype. Tracer-determined glucose disposal rates and hepatic glucose production show that peripheral tissues and livers from heterozygotes are more sensitive to the effects of insulin than wildtype. This mutation eliminates both DNA-binding and ligand-binding functions of the endogenous gene, concomitantly generating a lacZ reporter that faithfully recapitulates the endogenous expression pattern. Heterozygous mice or homozygous embryo-derived cells may be useful in studies of embryo and placental development, diabetes, atherosclerosis, inflammation, and for beta-galactosidase reporter function of the endogenous gene.

Development

A targeting vector was designed to insert a lacZ-neomycin resistance cassette into the second coding exon of the endogenous gene, just upstream of the DNA-binding domain. This construct was electroporated into 129S4/SvJae-derived J1 embryonic stem (ES) cells. Correctly targeted cells were injected into C57BL/6 blastocysts. Chimeric mice were backcrossed to C57BL/6 mice for more than 14 generations.

Allele

Symbol: Pparg^tm1Rev
Name: targeted mutation 1, Ronald M Evans
MGI accession ID: MGI:2149838
Generation method: Targeted
Attributes: Reporter; Null/Knockout
Marker symbol: Pparg
Marker name: peroxisome proliferator activated receptor gamma
Chromosome: 6
Strain of origin: 129S4/SvJae
Site of expression: lacZ expression closely mimics the patterns of the endogenous gene.
Molecular note: In-frame insertion of a lac Z-neomycin resistance cassette into the second coding exon of the gene, just upstream of the DNA binding domain, eliminated both DNA-binding and ligand-binding functions of the receptor. Whole-mount beta-galactosidase assays revealed conspicuous beta-gal activivity in the interscapular brown fat pad of only E14.5 embryos carrying a targeted allele, but not in wild-type embryos
General note: Complementation of Pparg^tm1Rev mutant embryos with wild-type placenta by tetraploid aggregation corrects the cardiac defect and extends viability to E12.5 (two mutants out of a total five), E15.5 (one out of ten) and at birth (one of six). Rescued embryos survive to term but exhibit a second lethal phase during the first week of life. Additional phenotypes include: a 30% reduction in body weight (P0-P4) and subsequent ill health (as shown by dehydration, weight loss and lethargy starting at P5) associated with lipodystrophy, a severly pale, distended and fatty liver, severe intestinal bleeding, and numerous focal hematomas throughout the brain (J:58223).