CByJ.129S7(B6)-Ldlr^tm1Her/J

Stock number: 012845
Research areas: Cardiovascular Research, Diabetes and Obesity Research, Internal/Organ Research, Metabolism Research, Mouse/Human Gene Homologs

Description

These BALB.LDLR knock-out mice may be useful for studying the effects of hyperlipidemia and hyperglycemia on diabetic nephrology and artherosclerosis.

Detailed description

In the BALB.LDLR^-/- strain, a neomycin (neo) selection cassette is inserted in exon 4 of the low density lipoprotein receptor (Ldlr) gene, abolishing endogenous gene function. Homozygous mice are viable, fertile, appear normal in size, and do not display any gross physical or behavioral abnormalities. On a 4% diet, BALB.LDLR^-/- mice have increased cholesterol (~200 mg/dl), increased triglycerides (~170mg/dl), and increased blood glucose (122 mg/dl) as compared with wildtype (WT). When moved onto a 21% fat diet these mice have cholesterol levels of 572 mg/dl, triglyceride levels of 180mg/dl, and blood glucose levels of 141 mg/dl. They exhibit renal injury, tubulointerstitial injury, and an increase in interstitial macrophages, and an increase in blood urea nitrogen when challenged with hyperlipidemia and hyperglycemia. When injected with Streptozotocin these mice also exhibit atherosclerotic lesions, aortic sinus lesions, and aortic fatty streak lesions caused by hyperlipidemia. These mice may be useful for studying the effects of hyperlipidemia and hyperglycemia on diabetic nephrology and artherosclerosis.

Development

A targeting vector was designed to insert neomycin (neo) selection cassette into exon 4 of the low density lipoprotein receptor (Ldlr) gene, abolishing gene function. This construct was electroporated into 129S7/SvEvBrd-Hprt1⁺-derived AB-1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts and chimeric males were bred with C57BL/6 females. The resulting offspring were backcrossed to C57BL/6 for at least 10 generations to establish a colony of Ldlr^-/- mice (Stock No. 002207). These mice were subsequently backcrossed to BALB/cByJ for at least 10 generations to establish a colony of BALB.LDLR^-/- mice. Upon arrival at The Jackson Laboratory, mice were bred with BALB/cByJ inbred mice (Stock No. 001026) for at least one generation to establish the colony.

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.