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*

(all 14)

PubMed

35098309 Full text @ Dis. Model. Mech.

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

Marker	Marker Type	Name
ltbp1	GENE	latent transforming growth factor beta binding protein 1
ltbp3	GENE	latent transforming growth factor beta binding protein 3
myl7	GENE	myosin, light chain 7, regulatory
nppa	GENE	natriuretic peptide A
nppb	GENE	natriuretic peptide B
serpine1	GENE	serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 1
tgfb1b	GENE	transforming growth factor, beta 1b
tgfbr2a	GENE	transforming growth factor beta receptor 2a
thbs1a	GENE	thrombospondin 1a

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Figures

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Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	chemical treatment by environment: LY 364947	Day 5	bulbus arteriosus bulbus arteriosus development decreased process quality, abnormal	Fig. 7
WT	chemical treatment by environment: LY 364947	Day 5	bulbus arteriosus increased diameter, abnormal	Fig. 7
WT	chemical treatment by environment: LY 364947	Day 5	bulbus arteriosus nucleus ab2-smad3 labeling increased amount, abnormal	Fig. 7
WT	chemical treatment by environment: LY 364947	Day 5	cardiac ventricle increased area, abnormal	Fig. 7
WT	chemical treatment by environment: LY 364947	Day 5	heart edematous, abnormal	Fig. 7
WT	chemical treatment by environment: LY 364947	Day 5	mandibular arch skeleton protruding, abnormal	Fig. 7
ltbp1^fb29/fb29; ltbp3^fb28/fb28	standard conditions	Protruding-mouth	bulbus arteriosus normal size, normal	Fig. 4
ltbp1^fb29/fb29; ltbp3^fb28/fb28	standard conditions	Protruding-mouth	bulbus arteriosus transforming growth factor beta receptor signaling pathway normal process quality, normal	Fig. 4
ltbp1^fb29/fb29; ltbp3^fb28/fb28	standard conditions	Protruding-mouth	cardiac ventricle normal size, normal	Fig. 4
ltbp1^fb29/fb29; ltbp3^fb28/fb28	standard conditions	Day 4	bulbus arteriosus increased diameter, abnormal	Fig. 5

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
fb18Tg	Tg2(myl7:NLS-EGFP)	Transgenic Insertion
fb28		Small Deletion	ltbp3
fb29		Small Deletion	ltbp1
y7Tg	Tg(fli1:nEGFP)	Transgenic Insertion

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
thoracic aortic aneurysm	ltbp1^fb29/fb29; ltbp3^fb28/fb28	standard conditions	TAS

Sequence Targeting Reagents

Target	Reagent	Reagent Type
ltbp1	CRISPR3-ltbp1	CRISPR
ltbp3	TALEN1-ltbp3	TALEN

Fish

Fish
fb18Tg
ltbp1^fb29/fb29; ltbp3^fb28/fb28
ltbp1^fb29/fb29; ltbp3^fb28/fb28; fb18Tg
ltbp1^fb29/fb29; ltbp3^fb28/fb28; y7Tg
WT
y7Tg

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP

Mapping

Abrial et al., 2022 ZDB-PUB-220202-19 PMID:35098309

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

Abrial et al., 2022

ZDB-PUB-220202-19
PMID:35098309