PUBLICATION
Latent TGFβ binding proteins 1 and 3 protect the larval zebrafish outflow tract from aneurysmal dilatation
- Authors
- Abrial, M., Basu, S., Huang, M., Butty, V., Schwertner, A., Jeffrey, S., Jordan, D., Burns, C.E., Burns, C.G.
- ID
- ZDB-PUB-220202-19
- Date
- 2022
- Source
- Disease models & mechanisms 15(3): (Journal)
- Registered Authors
- Burns (Erter), Caroline, Burns, Geoff
- Keywords
- LTBP proteins, Outflow tract, TGFβ signaling, Thoracic aortic aneurysm, Zebrafish
- Datasets
- GEO:GSE152389
- MeSH Terms
-
- Animals
- Aortic Aneurysm, Thoracic*/genetics
- Aortic Aneurysm, Thoracic*/metabolism
- Aortic Aneurysm, Thoracic*/pathology
- Dilatation
- Humans
- Larva/metabolism
- Latent TGF-beta Binding Proteins/genetics
- Latent TGF-beta Binding Proteins/metabolism*
- Marfan Syndrome*/pathology
- Mice
- Transforming Growth Factor beta/metabolism
- Zebrafish/metabolism
- Zebrafish Proteins/metabolism*
- PubMed
- 35098309 Full text @ Dis. Model. Mech.
Citation
Abrial, M., Basu, S., Huang, M., Butty, V., Schwertner, A., Jeffrey, S., Jordan, D., Burns, C.E., Burns, C.G. (2022) Latent TGFβ binding proteins 1 and 3 protect the larval zebrafish outflow tract from aneurysmal dilatation. Disease models & mechanisms. 15(3):.
Abstract
Aortic root aneurysm is a common cause of morbidity and mortality in Loeys-Dietz and Marfan Syndromes, where perturbations in TGFβ signaling play a causal or contributory role, respectively. Despite the advantages of cross-species disease modeling, animal models of aortic root aneurysm are largely restricted to genetically engineered mice. Here, we report that zebrafish devoid of latent TGFβ binding protein (ltbp) 1 and 3 develop rapid and severe aneurysm of the outflow tract (OFT), the aortic root equivalent. Similar to syndromic aneurysm tissue, the distended OFTs display evidence for paradoxical hyperactivated TGFβ signaling. RNA-sequencing revealed significant overlap between the molecular signatures of disease tissue from mutant zebrafish and Marfan mice. Lastly, chemical inhibition of TGFβ signaling in wild-type animals phenocopied mutants but chemical activation did not, demonstrating that TGFβ signaling is protective against aneurysm. Human relevance is supported by recent studies implicating genetic lesions in LTBP3 and potentially LTBP1 as heritable causes of aortic root aneurysm. Ultimately, our data demonstrate that zebrafish can now be leveraged to interrogate thoracic aneurysmal disease and identify novel lead compounds through small molecule suppressor screens.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping