B6.129-Akt2^tm1.1Mbb Ldlr^tm1Her/J

Stock number: 006952
Research areas: Cardiovascular Research, Diabetes and Obesity Research, Metabolism Research, Mouse/Human Gene Homologs, Research Tools

Description

These mice harbor knock-out mutations in both the Akt2 (thymoma viral proto-oncogene 2) and Ldlr (low density lipoprotein receptor), and may be useful in studies of diabetes, metabolism, hyperglycemia, and atherosclerosis.

Detailed description

Independently, homozygous Akt2 mutant mice develop insulin resistance and diabetes, while LDLR homozygotes are predisposed to atherosclerosis. Double mutant mice that are heterozygous for the Akt2 allele and homozygous for the LDLR mutation are viable and fertile. These double mutant mice may be useful in studies of diabetes, metabolism, hyperglycemia, and atherosclerosis.

Development

The Ldlr^tm1Her mutation was made by Dr. Robert Hammer and Joachim Herz (HHMI, University of Texas Southwestern Medical Center). Briefly, a targeting vector was used to insert a neo cassette into exon 4. The vector was electroporated into 129S7/SvEvBrd-derived AB1 embryonic stem (ES) cells. Chimeric mice were bred to C57BL/6J, and the strain was made congenic on a C57BL/6J genetic background at The Jackson Laboratory (Stock No. 002207). The Akt2 mutant strain was created by Dr. Morris Birnbaum (University of Pennsylvania) by flanking exons 4-5 with loxP sites. The targeting vector was electroporated into 129P2/OlaHsd-derived E14 embryonic stem (ES) cells, and the chimeric males were bred with C57BL/6 females. Mutant mice were then bred to cre transgenic mice to remove exons 4-5 and bred for an unknown number of generations. Akt2 mutant mice on a mixed (approximately 80% C57BL/6J) background were shipped to Dr. Jan Breslow at The Rockefeller University. To generate the double mutant strain, Stock No. 002207 mice were bred with Akt2 mutant mice in the laboratory of Dr. Jan Breslow at The Rockefeller University. Double mutant mice were then backcrossed to C57BL/6J for approximately 7 generations prior to arrival at The Jackson Laboratory. The donating investigators indicate that 102/10 4 microsatellite markers indicate C57BL/6J background; the only exceptions are D7Mit21 and D7Mit294. The Y chromosome may not have been fixed to the C57BL/6J genetic background.

Allele

Symbol: Ldlr^tm1Her
Name: targeted mutation 1, Joachim Herz
MGI accession ID: MGI:1857212
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Ldlr
Marker name: low density lipoprotein receptor
Chromosome: 9
Strain of origin: 129S7/SvEvBrd-Hprt⁺
Site of expression: Immunoblot analysis of liver membranes detected a truncated protein in homozygous mutant animals.
Molecular note: Insertion of a neomycin resistance cassette into exon 4. The authors predict that the targeted allele would encode a truncated non-functional protein that will not bind LDL, and that lacks a membrane spanning segment. Immunoblot analysis of liver membranes detected a truncated protein in homozygous mutant animals.
General note: When used in bone marrow transplant into Ldlr^tm1Her homozygous mice, Abca1^tm1Jdm Abcg1^tm1Dgen homozygous cells accelerate the development of atherosclerosis. (J:130777)

Phenotypic Similarity to Human Syndrome: Atherosclerosis, Susceptibility to J:29950, J:225091 in mice fed a high-cholesterol diet.

Allele

Symbol: Akt2^tm1.1Mbb
Name: targeted mutation 1.1, Morris J Birnbaum
MGI accession ID: MGI:2158456
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Akt2
Marker name: thymoma viral proto-oncogene 2
Chromosome: 7
Strain of origin: 129P2/OlaHsd
Molecular note: This allele is a derivative of Akt2^tm1Mbb. Cre-mediated recombination in vivo under the control of a 6 kb 5'-flanking sequence from the Pou3f4 gene excised the floxed exons 4 and 5 in the germline. The excision of exons 4 and 5 results in a frameshift mutation that would lead to a premature termination even if the remaining exon 3 were to splice to exon 6. Exon 5 encodes the lysine residue necessary for catalytic activity. Western blot analyses using a polyclonal antibody did not detect protein in liver, muscle, and isolated adipocytes from homozygous mice.