Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Systematic disruption of zebrafish fibrillin genes identifies a translational zebrafish model for Marfan syndrome

ABSTRACT: 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.

ORGANISM(S): Danio rerio

PROVIDER: GSE300393 | GEO | 2025/06/27

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Murine Marfan Syndrome Sildenafil Treatment

Project description:Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 (Fbn1) gene. While aortic rupture is the major cause of mortality in MFS, patients also suffer from poorly understood pulmonary complications. Loss of basal nitric oxide (NO) production and vascular integrity are proposed to take part in MFS aortic root disease, yet their contribution to lung complications has yet to be determined. Due to its capacity to potentiate the vasodilatory NO/cyclic guanylate monophosphate signaling pathway, we assessed whether the phosphodiesterase-5 (PDE5) inhibitor sildenafil (SIL) could attenuate aortic root remodelling and emphysema in a mouse model of MFS. Despite increasing NO-dependent vasodilation, SIL unexpectedly elevated mean arterial blood pressure, failed to inhibit MFS aortic root dilation and exacerbated elastic fibrefiber fragmentation. In the lung, early pulmonary artery dilation observed in untreated MFS mice was delayed by SIL treatment, and severe emphysema-like alveolar destruction was prevented. In addition, improvements in select parameters of lung function were documented. Subsequent micro-array analyses showed changes to gene signatures involved in the inflammatory response in MFS lung treated with SIL, without significant downregulation of connective tissue or TGF-β signalling genes. Since PDE5 inhibition leads to improved lung histopathology and function, the effects of SIL against emphysema warrant further investigation in the settings of MFS despite limited efficacy on aortic root remodelling.

2019-03-19 | GSE128481 | GEO

Systematic disruption of zebrafish fibrillin genes identifies a translational zebrafish model for Marfan syndrome

Project description:Systematic disruption of zebrafish fibrillin genes identifies a translational zebrafish model for Marfan syndrome

| PRJNA1280187 | ENA

A Marfan syndrome gene expression phenotype in cultured skin fibroblasts

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

Ang II type 1a receptor in Marfan syndrome

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

Fibrillin-1 deficient mice

Project description:Different fibrillin-1 mutant mice Keywords: other

2004-10-20 | GSE1852 | GEO

Transcription profiling of mouse deficient for Fibrillin-1

Project description:Different fibrillin-1 mutant mice

2008-06-11 | E-GEOD-1852 | biostudies-arrayexpress

Marfan syndrome in mice

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

The RGD sequence in fibrillin-1 regulates miRNA expression

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

The RGD sequence in fibrillin-1 regulates mRNA expression

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

Latent TGF β binding proteins 1 and 3 protect the larval zebrafish outflow tract from aneurysmal dilatation

Project description:Aneurysm and dissection of the aortic root is a common cause of morbidity and mortality in Loeys-Dietz Syndrome (LDS) and Marfan Syndrome (MFS), where perturbations in TGF β signaling play a causal or contributory role, respectively. Despite the advantages of cross-species disease modeling for mechanistic studies and pre-clinical drug discovery, animal models of aortic root aneurysm are largely restricted to genetically engineered mice. Here, we report that zebrafish larvae, homozygous for null mutations in latent TGF β binding proteins (ltbps) 1 and 3, develop rapid and severe aneurysmal dilatation of the aortic root equivalent, the outflow tract (OFT), after grossly unperturbed cardiac morphogenesis. The ventricle also becomes significantly dilated and upregulates stress-responsive genes, which likely reflects compensatory pathologic remodeling since ltbp1 and ltbp3 co-expression is restricted to the OFT. Similar to aneurysm tissue from LDS and MFS patients, the distended OFTs display evidence for hyperactivated TGF β signaling. Moreover, RNA-sequencing revealed significant overlap between the molecular signatures of diseased tissue from double knockout zebrafish and MFS mice. Lastly, chemical inhibition of the TGF β Type I receptor in wild-type embryos evoked similar OFT and ventricular dilation phenotypes, demonstrating that TGF β signaling is protective against these pathologies. The disease relevance of the mutant phenotype is further supported by recent family studies implicating genetic lesions in Ltbp3, and likely Ltbp1, as heritable causes of aortic root aneurysm. Ultimately, our data demonstrate that the unique advantages of zebrafish can now be leveraged to interrogate thoracic aneurysmal disease and identify novel lead compounds through small molecule suppressor screens.

2022-04-19 | GSE152389 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data