B6.Cg-Ldlr^tm1Her Tg(Tagln-Pth1r*)2Towl/J

Stock number: 022488
Research areas: Cardiovascular Research, Diabetes and Obesity Research, Metabolism Research, Mouse/Human Gene Homologs

Description

This compound mutant strain expresses the constitutively active H223R mutant form of Pth1r (parathyroid hormone 1 receptor) under the regulatory control of the vascular smooth muscle-specific mouse SM22 (Tagln, transgelin) promoter as well as a knockout of the Ldlr gene. This strain demonstrates that cell-autonomous vascular smooth muscle cell PTHR1 activity inhibits arteriosclerotic Wnt/β-catenin signaling and reduces vascular oxidative stress, thus limiting aortic type I collagen and calcium accrual in diabetic LDLR-deficient mice.

Detailed description

Vascular fibrosis and calcification contribute to diabetic arteriosclerosis, impairing distal tissue perfusion. Ldlr knockout mice serve as a model for this arterial calcification. Males fed a high fat Western diet develop obesity, diabetes, hyperinsulinemia, hypertriglyceridemia and hypercholesterolemia with progressively severe arterial calcification. Wnt (wingless-related MMTV) gene family members, up-regulated in arteries by the low-grade inflammation of "diabesity", stimulate type I collagen expression and osteogenic mineralization of mesenchymal progenitors via β-catenin (Ctnnb1, catenin (cadherin associated protein), beta 1). Conversely, parathyroid hormone (PTH) inhibits aortic calcification in LDLR (low density lipoprotein receptor)-deficient mice fed high fat diabetogenic diets (HFD).

This compound mutant strain expresses the constitutively active H223R mutant form of Pth1r (parathyroid hormone 1 receptor) under the regulatory control of the vascular smooth muscle-specific mouse SM22 (Tagln, transgelin) promoter as well as a knockout of the Ldlr gene. It was constructed to determine the impact of vascular PTHR1 activity on arteriosclerotic Wnt/β-catenin signaling.

This strain demonstrates that cell-autonomous vascular smooth muscle cell PTHR1 activity inhibits arteriosclerotic Wnt/β-catenin signaling and reduces vascular oxidative stress, thus limiting aortic type I collagen and calcium accrual in diabetic LDLR-deficient mice.

Development

The vascular smooth muscle cell-specific mouse Tagln (SM22) promoter drives expression of a 1.8 kb cDNA encoding the open reading frame of the H223R constitutively active form of mouse Pthr1 (which does not require ligand for activation) upstream of rabbit beta-globin 3'UTR and polyA sequences. The mutation was made via male C57BL/6 pronuclear injection. Transgenic animals were intercrossed with C57BL/6 background Ldlr^tm1Her animals (see Stock No. 002207). This strain was maintained on a C57BL/6 genetic background by the donating laboratory.

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-Hprt1⁺
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: Tg(Tagln-Pth1r*)2Towl
Name: transgene insertion 2, Dwight Towler
MGI accession ID: MGI:5509011
Generation method: Transgenic
Attributes: Constitutively active; Inserted expressed sequence
Marker symbol: Tg(Tagln-Pth1r*)2Towl
Marker name: transgene insertion 2, Dwight Towler
Chromosome: UN
Strain of origin: C57BL/6
Expressed genes: Pth1r,parathyroid hormone 1 receptor,mouse, laboratory
Molecular note: The vascular smooth muscle cell-specific mouse Tagln (SM22) promoter was used to drive expression of a 1.8 kb cDNA encoding the open reading frame of the H223R constitutively active form of mouse Pthr1 upstream of rabbit beta-globin 3'UTR and polyA sequences.