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

ABSTRACT: 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.

ORGANISM(S): Danio rerio

PROVIDER: GSE152389 | GEO | 2022/04/19

REPOSITORIES: GEO