Absence of Cardiovascular Manifestations in a Haploinsufficient Tgfbr1 Mouse Model
نویسندگان
چکیده
Loeys-Dietz syndrome (LDS) is an autosomal dominant arterial aneurysm disease belonging to the spectrum of transforming growth factor β (TGFβ)-associated vasculopathies. In its most typical form it is characterized by the presence of hypertelorism, bifid uvula/cleft palate and aortic aneurysm and/or arterial tortuosity. LDS is caused by heterozygous loss of function mutations in the genes encoding TGFβ receptor 1 and 2 (TGFBR1 and -2), which lead to a paradoxical increase in TGFβ signaling. To address this apparent paradox and to gain more insight into the pathophysiology of aneurysmal disease, we characterized a new Tgfbr1 mouse model carrying a p.Y378* nonsense mutation. Study of the natural history in this model showed that homozygous mutant mice die during embryonic development due to defective vascularization. Heterozygous mutant mice aged 6 and 12 months were morphologically and (immuno)histochemically indistinguishable from wild-type mice. We show that the mutant allele is degraded by nonsense mediated mRNA decay, expected to result in haploinsufficiency of the mutant allele. Since this haploinsufficiency model does not result in cardiovascular malformations, it does not allow further study of the process of aneurysm formation. In addition to providing a comprehensive method for cardiovascular phenotyping in mice, the results of this study confirm that haploinsuffciency is not the underlying genetic mechanism in human LDS.
منابع مشابه
Tgfbr1 haploinsufficiency inhibits the development of murine mutant Kras-induced pancreatic precancer.
To dissect the role of constitutively altered Tgfbr1 signaling in pancreatic cancer development, we crossed Elastase-Kras(G12D) (EL-Kras) mice with Tgfbr1 haploinsufficient mice to generate EL-Kras/Tgfbr1(+/-) mice. Mice were euthanized at 6 to 9 months to compare the incidence, frequency, and size of precancerous lesions in the pancreas. Only 50% of all EL-Kras/Tgfbr1(+/-) mice developed prein...
متن کاملConstitutively active transforming growth factor β receptor 1 in the mouse ovary promotes tumorigenesis
Despite the well-established tumor suppressive role of TGFβ proteins, depletion of key TGFβ signaling components in the mouse ovary does not induce a growth advantage. To define the role of TGFβ signaling in ovarian tumorigenesis, we created a mouse model expressing a constitutively active TGFβ receptor 1 (TGFBR1) in ovarian somatic cells using conditional gain-of-function approach. Remarkably,...
متن کاملStandardized Punica Granatum Pericarp Extract, Suppresses Tumor Proliferation and Angiogenesis in a Mouse Model of Melanoma: Possible Involvement of PPARα and PPARγ Pathways
Melanoma is a challenging disease to treat. Punica granatum L. has a potential anticancer effect. This study determined the antiproliferative and antiangiogenic potential of the extract from pomegranate peel (PPE) in melanoma. Melanoma cells (1 × 106) were injected to C57BL6 mice subcutaneously. On 8th day, mice were randomly divided into 9 groups. Group 1 was considered as control and received...
متن کاملStandardized Punica Granatum Pericarp Extract, Suppresses Tumor Proliferation and Angiogenesis in a Mouse Model of Melanoma: Possible Involvement of PPARα and PPARγ Pathways
Melanoma is a challenging disease to treat. Punica granatum L. has a potential anticancer effect. This study determined the antiproliferative and antiangiogenic potential of the extract from pomegranate peel (PPE) in melanoma. Melanoma cells (1 × 106) were injected to C57BL6 mice subcutaneously. On 8th day, mice were randomly divided into 9 groups. Group 1 was considered as control and received...
متن کاملChemopreventive and chemotherapeutic actions of mTOR inhibitor in genetically defined head and neck squamous cell carcinoma mouse model.
PURPOSE To assess the efficacy of rapamycin treatment in chemoprevention and chemotherapy of tumorigenesis in a genetically defined mouse model of head and neck squamous cell carcinoma (HNSCC). EXPERIMENTAL DESIGN Knockdown of Tgfbr1 and/or Pten using siRNA-mediated RNA interference was carried out in human HNSCC cell lines to analyze molecular changes in the mTOR pathway. Tgfbr1(flox/flox); ...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره 9 شماره
صفحات -
تاریخ انتشار 2014