Latent TGF ß binding proteins 1 and 3 protect the larval zebrafish outflow tract   from aneurysmal dilatation
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 ß 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 ß 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 ß     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 ß Type I receptor in wild-type embryos evoked   similar OFT and ventricular dilation phenotypes, demonstrating that TGF ß 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. Overall design: Dissected ventricles and outflow tracts from 5 days post-fertilization sibling control and ltbp1-/-; ltbp3-/- double knockout zebrafish were profiled by RNA-Seq