Systematic disruption of zebrafish fibrillin genes identifies a translational zebrafish model for Marfan syndrome
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ABSTRACT:
PROVIDER: PRJNA1280187 | ENA |
REPOSITORIES: ENA
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Project description:Fibrillin dysfunction in Marfan syndrome (MFS) causes severe cardiovascular complications, including aortic dilation, dissection, and rupture. To model MFS, we generated zebrafish mutants lacking various fibrillin genes. Among them, fibrillin-2b-deficient zebrafish exhibited cardiovascular phenotypes resembling those seen in patients with MFS. Multimodal imaging revealed early cardiac defects, bulbus arteriosus dilation, and valve abnormalities. RNA sequencing identified developmental disruptions, and compound testing demonstrated the model’s potential for drug discovery. This zebrafish model, recapitulating key cardiovascular features of MFS, provides a valuable platform for investigating disease mechanisms and identifying novel treatment strategies.
2025-06-27 | GSE300393 | GEO
Project description:Fibrillins are the major components of microfibrils in the extracellular matrix of elastic and non-elastic tissues. Fibrillin-1 contains one evolutionarily conserved Arg-Gly-Asp (RGD) sequence which mediates cell-matrix interactions through cell-surface integrins. Mutations in close vicinity to the RDG sequence lead to heritable disorders, including Marfan syndrome and stiff skin syndrome. Two recombinant fibrillin-1 fragments were produced, one wild-type RGD-containing fragment and one fragment containing a mutant RGA sequence, which has been previously shown to abolish interactions with integrins. To determine the differential regulation of signaling pathways, microarray analysis of microRNA expression was conducted using Affymetrix miRNA3.0 chips. The microRNA expression levels were compared after 24 hours of interaction between human skin fibroblasts (HSFs) and the RGD- and RGA-containing fibrillin-1 fragments.
2018-12-10 | GSE82083 | GEO
Project description:Fibrillins are the major components of microfibrils in the extracellular matrix of elastic and non-elastic tissues. Fibrillin-1 contains one evolutionarily conserved Arg-Gly-Asp (RGD) sequence which mediates cell-matrix interactions through cell-surface integrins. Mutations in close vicinity to the RDG sequence lead to heritable disorders, including Marfan syndrome and stiff skin syndrome. Two recombinant fibrillin-1 fragments were produced, one wild-type RGD-containing fragment and one fragment containing a mutant RGA sequence, which has been previously shown to abolish interactions with integrins. To determine the differential regulation of signaling pathways, microarray analysis of mRNA expression was conducted using Affymetrix Human Gene 2.0 ST chips. The mRNA expression levels were compared after 24 hours of interaction between human skin fibroblasts (HSFs) and the RGD- and RGA-containing fibrillin-1 fragments.
2018-12-10 | GSE82079 | GEO
Project description:Using Cdh5-Cre and Sm22-Cre transgenes to characterize the impact of disruption of the angiotensin II type 1a receptor (AT1ar) in vascular endothelial and smooth muscle cells, respectively, of wild type (WT) mice compared to fibrillin-1 hypomorphic mice (Fbn1mgR/mgR mice) that replicate early onset progressively severe Marfan syndrome (MFS) with dissecting thoracic aortic aneurysm (TAA).
2018-01-30 | GSE109797 | GEO
Project description:Mutations in the fibrillin-1 gene result in cardiovascular, ocular, and skeletal abnormalities in Marfan syndrome. Here we show that a fibrillin-1 mutation also alters the neovessel formation. In the mouse retina vascularization model, fibrillin-1 is detected at the basement membrane underlying the angiogenic front and around arterioles. In Fbn1C1041G/+ mice, a model of Marfan disease, the microvasculature is altered at these sites. At the front, endothelial tip-cell sprouting and branching are decreased, and we show that mutant fibrillin-1 delays angiogenesis by affecting Notch signalling. Supplying the growing vasculature of Fbn1C1041G/+ mice with a C-terminal fragment of fibrillin-1 corrects all defects. In vitro, the C-terminal fragment of fibrillin-1 also displays pro-angiogenic activities on microvascular endothelial cell. Our data establish that fibrillin-1 performs essential functions in microvessel formation and integrity and that mutant fibrillin-1-induced defects can be rescued pharmacologically.
2023-05-31 | PXD029834 | Pride
Project description:Background: Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in the fibrillin-1 gene. This syndrome constitutes a significant identifiable subtype of aortic aneurysmal disease, accounting for over 5% of ascending and thoracic aortic aneurysms. Results: We used spotted membrane DNA macroarrays to identify genes whose altered expression levels may contribute to the phenotype of the disease. Our analysis of 4132 genes identified a subset with significant expression differences between skin fibroblast cultures from unaffected controls versus cultures from affected individuals with known fibrillin-1 mutations. Subsequently, 10 genes were chosen for validation by quantitative RT-PCR. Conclusions: Differential expression of many of the validated genes was associated with MFS samples when an additional group of unaffected and MFS affected subjects were analyzed (p-value < 3 x 10-6 under the null hypothesis that expression levels in cultured fibroblasts are unaffected by MFS status). An unexpected observation was the range of individual gene expression. In unaffected control subjects, expression ranges exceeding 10 fold were seen in many of the genes selected for qRT-PCR validation. The variation in expression in the MFS affected subjects was even greater. Keywords: disease state comparison; Marfan syndrome; cultured skin fibroblasts
2007-09-14 | GSE8759 | GEO
Project description:Different fibrillin-1 mutant mice Keywords: other
2004-10-20 | GSE1852 | GEO
Project description:Different fibrillin-1 mutant mice
2008-06-11 | E-GEOD-1852 | biostudies-arrayexpress
Project description:Comparison of whole genome expression profiles to characterize gene expression during development of thoracic aortic aneurysm in fibrillin-1 hypomorphic mice (Fbn1mgR/mgR).
2018-01-27 | GSE109722 | GEO