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.
Dwight A Towler, Sanford-Burnham Medical Research Institute
Genetic Background | Generation |
---|---|
|
Allele Type | Gene Symbol | Gene Name |
---|---|---|
Targeted (Null/Knockout) | Ldlr | low density lipoprotein receptor |
Allele Type |
---|
Transgenic (Constitutively active, Inserted expressed sequence) |
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.
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 Ldlrtm1Her animals
(see Stock No. 002207). This strain was maintained on a C57BL/6 genetic background by the donating laboratory.
Expressed Gene | Pth1r, parathyroid hormone 1 receptor, mouse, laboratory |
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Site of Expression |
Allele Name | targeted mutation 1, Joachim Herz |
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Allele Type | Targeted (Null/Knockout) |
Allele Synonym(s) | LDLR-; LDLR KO; LDLr0; LDLrKO; LDLr-KO; Ldlrtm1Her |
Gene Symbol and Name | Ldlr, low density lipoprotein receptor |
Gene Synonym(s) | |
Site of Expression | Immunoblot analysis of liver membranes detected a truncated protein in homozygous mutant animals. |
Strain of Origin | 129S7/SvEvBrd-Hprt+ |
Chromosome | 9 |
General Note | When used in bone marrow transplant into Ldlrtm1Her homozygous mice, Abca1tm1Jdm Abcg1tm1Dgen 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. |
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. |
Mutations Made By | Dr. Joachim Herz, Univ of Texas Southwest Med Ctr Dallas |
Allele Name | transgene insertion 2, Dwight Towler |
---|---|
Allele Type | Transgenic (Constitutively active, Inserted expressed sequence) |
Allele Synonym(s) | |
Gene Symbol and Name | Tg(Tagln-Pth1r*)2Towl, transgene insertion 2, Dwight Towler |
Gene Synonym(s) | |
Promoter | Tagln, transgelin, mouse, laboratory |
Expressed Gene | Pth1r, parathyroid hormone 1 receptor, mouse, laboratory |
Strain of Origin | C57BL/6 |
Chromosome | UN |
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. |
Heterozygous/hemizygous and homozygous/homozygous mice are viable and fertile.
When using the B6.Cg-Ldlrtm1Her Tg(Tagln-Pth1r*)2Towl/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #022488 in your Materials and Methods section.
Facility Barrier Level Descriptions
Service/Product | Description | Price |
---|---|---|
Heterozygous for Ldlr<tm1Her>, Hemizygous or Non carrier for Tg(Tagln-Pth1r*)2Towl |
Frozen Mouse Embryo | B6.Cg-Ldlr<tm1Her> Tg(Tagln-Pth1r*)2Towl/J Frozen Embryo | $2595.00 |
Frozen Mouse Embryo | B6.Cg-Ldlr<tm1Her> Tg(Tagln-Pth1r*)2Towl/J Frozen Embryo | $2595.00 |
Frozen Mouse Embryo | B6.Cg-Ldlr<tm1Her> Tg(Tagln-Pth1r*)2Towl/J Frozen Embryo | $3373.50 |
Frozen Mouse Embryo | B6.Cg-Ldlr<tm1Her> Tg(Tagln-Pth1r*)2Towl/J Frozen Embryo | $3373.50 |
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