PUBLICATION

The pro-inflammatory signalling regulator Stat4 promotes vasculogenesis of great vessels derived from endothelial precursors

Authors

Meng, Z.Z., Liu, W., Xia, Y., Yin, H.M., Zhang, C.Y., Su, D., Yan, L.F., Gu, A.H., Zhou, Y.

ID

ZDB-PUB-170304-2

Date

2017

Source

Nature communications 8: 14640 (Journal)

Registered Authors

Zhou, Yong

Keywords

Cell growth, Differentiation, Disease model

MeSH Terms

Cell Proliferation/genetics
Zebrafish
Animals, Genetically Modified
Animals
Histone Deacetylases/genetics
Histone Deacetylases/metabolism
STAT4 Transcription Factor/genetics
STAT4 Transcription Factor/metabolism
STAT4 Transcription Factor/physiology*
Morphogenesis/genetics*
Zebrafish Proteins/genetics
Zebrafish Proteins/metabolism*
Endothelial Cells/physiology
Branchial Region/blood supply
Branchial Region/growth & development
Homeobox Protein Nkx-2.5/genetics
Homeobox Protein Nkx-2.5/metabolism
Gene Expression Regulation, Developmental*
Cardiovascular Diseases/genetics*
Morpholinos/genetics
Mesoderm/cytology
Mesoderm/growth & development
Arteries/abnormalities
Arteries/growth & development*
Embryo, Nonmammalian
Cell Differentiation/genetics
Models, Animal
Gene Knockdown Techniques

(all 28)

PubMed

28256502 Full text @ Nat. Commun.

Abstract

Vasculogenic defects of great vessels (GVs) are a major cause of congenital cardiovascular diseases. However, genetic regulators of endothelial precursors in GV vasculogenesis remain largely unknown. Here we show that Stat4, a transcription factor known for its regulatory role of pro-inflammatory signalling, promotes GV vasculogenesis in zebrafish. We find stat4 transcripts highly enriched in nkx2.5⁺ endothelial precursors in the pharynx and demonstrate that genetic ablation of stat4 causes stenosis of pharyngeal arch arteries (PAAs) by suppressing PAAs 3-6 angioblast development. We further show that stat4 is a downstream target of nkx2.5 and that it autonomously promotes proliferation of endothelial precursors of the mesoderm. Mechanistically, stat4 regulates the emerging PAA angioblasts by inhibiting the expression of hdac3 and counteracting the effect of stat1a. Altogether, our study establishes a role for Stat4 in zebrafish great vessel development, and suggests that Stat4 may serve as a therapeutic target for GV defects.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
atrip	AB/TU	standard conditions	High-pec	whole organism	RTPCR	Fig. 7
atrip	AB/TU + MO1-stat4	standard conditions	High-pec	whole organism	RTPCR	Fig. 7
cdk2	AB/TU	standard conditions	High-pec	whole organism	RTPCR	Fig. 7
cdk2	AB/TU + MO1-stat4	standard conditions	High-pec	whole organism	RTPCR	Fig. 7
cdkn1ca	AB/TU	standard conditions	High-pec	whole organism	RTPCR	Fig. 7
cdkn1ca	AB/TU + MO1-stat4	standard conditions	High-pec	whole organism	RTPCR	Fig. 7
cdkn2a/b	AB/TU	standard conditions	High-pec	whole organism	RTPCR	Fig. 7
cdkn2a/b	AB/TU + MO1-stat4	standard conditions	High-pec	whole organism	RTPCR	Fig. 7
DsRed	stat4^{zf2070/zf2070}; y1Tg; zf2071Tg	standard conditions	Pec-fin	aortic arch blood cell	IFL	Fig. 2
DsRed	stat4^{zf2070/zf2070}; zf2071Tg	standard conditions	Pec-fin	aortic arch blood cell	IFL	Fig. 2

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB/TU	chemical treatment by environment: (R)-lisofylline	High-pec	aortic arch 3 angioblast cell differentiation occurrence, normal	Fig. 7
AB/TU	chemical treatment by environment: (R)-lisofylline	High-pec	aortic arch 4 angioblast cell differentiation occurrence, normal	Fig. 7
AB/TU	chemical treatment by environment: (R)-lisofylline	High-pec	aortic arch 5 angioblast cell differentiation occurrence, normal	Fig. 7
AB/TU	chemical treatment by environment: (R)-lisofylline	High-pec	aortic arch 6 apoptotic process occurrence, normal	Fig. 7
AB/TU + MO1-stat4	standard conditions	High-pec	aortic arch 3 angioblast cell differentiation decreased occurrence, abnormal	Fig. 3
AB/TU + MO1-stat4	standard conditions	High-pec	aortic arch 3 vasculogenesis decreased occurrence, abnormal	Fig. 3
AB/TU + MO1-stat4	standard conditions	High-pec	aortic arch 4 angioblast cell differentiation decreased occurrence, abnormal	Fig. 3
AB/TU + MO1-stat4	standard conditions	High-pec	aortic arch 4 vasculogenesis decreased occurrence, abnormal	Fig. 3
AB/TU + MO1-stat4	standard conditions	High-pec	aortic arch 5 angioblast cell differentiation decreased occurrence, abnormal	Fig. 3
AB/TU + MO1-stat4	standard conditions	High-pec	aortic arch 5 vasculogenesis decreased occurrence, abnormal	Fig. 3

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
fb7Tg	TgBAC(-36nkx2.5:ZsYellow)	Transgenic Insertion
y1Tg	Tg(fli1:EGFP)	Transgenic Insertion
y7Tg	Tg(fli1:nEGFP)	Transgenic Insertion
zf2070		Small Deletion	stat4
zf2071Tg	Tg3(gata1a:DsRed)	Transgenic Insertion
zf2072Tg	Tg9(kdrl:mCherry)	Transgenic Insertion
zf2073Tg	Tg(tcf21:GFP)	Transgenic Insertion

1 - 7 of 7

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Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
hdac3	MO3-hdac3	MRPHLNO
nkx2.5	MO3-nkx2.5	MRPHLNO
stat1a	MO2-stat1a	MRPHLNO
stat1b	MO2-stat1b	MRPHLNO
stat4	CRISPR1-stat4	CRISPR
stat4	MO1-stat4	MRPHLNO

Fish

Fish
AB/TU
AB/TU + MO1-stat4
AB/TU + MO1-stat4 + MO3-nkx2.5
AB/TU + MO3-nkx2.5
fb7Tg
fb7Tg + MO1-stat4
stat4^zf2070/+
stat4^zf2070/+; zf2072Tg
stat4^{zf2070/zf2070}
stat4^{zf2070/zf2070} + MO2-stat1a

1 - 10 of 20

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Antibodies

Name	Type	Antigen Genes	Isotypes	Host Organism
Ab1-hdac3	monoclonal		IgG	Rabbit
Ab1-stat1a	polyclonal		IgG	Rabbit
Ab2-nkx2.5	polyclonal	nkx2.5	IgG	Rabbit

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
DsRed	EFG	DsRed
EGFP	EFG	EGFP
GFP	EFG	GFP
mCherry	EFG	mCherry
ZsYellow	EFG	ZsYellow

Mapping

Meng et al., 2017 ZDB-PUB-170304-2 PMID:28256502

The pro-inflammatory signalling regulator Stat4 promotes vasculogenesis of great vessels derived from endothelial precursors

Meng et al., 2017

ZDB-PUB-170304-2
PMID:28256502