PUBLICATION

Extracellular bone morphogenetic protein modulator BMPER and twisted gastrulation homolog 1 preserve arterial venous specification in zebrafish blood vessel development and regulate Notch signaling in endothelial cells

Authors

Esser, J.S., Steiner, R.E., Deckler, M., Schmitt, H., Engert, B., Link, S., Charlet, A., Patterson, C., Bode, C., Zhou, Q., Moser, M.

ID

ZDB-PUB-180224-5

Date

2018

Source

The FEBS journal 285(8): 1419-1436 (Journal)

Registered Authors

Keywords

NICD, AV malformation, DMH1, Ephrins, HUVECs

MeSH Terms

Animals
Animals, Genetically Modified
Bone Morphogenetic Proteins/genetics*
Bone Morphogenetic Proteins/metabolism
Carrier Proteins/genetics*
Carrier Proteins/metabolism
Cells, Cultured
Embryo, Nonmammalian/blood supply
Embryo, Nonmammalian/embryology
Embryo, Nonmammalian/metabolism
Endothelial Cells/metabolism*
Gene Expression Regulation, Developmental
Humans
In Situ Hybridization
Neovascularization, Physiologic/genetics*
RNA Interference
Receptors, Notch/genetics*
Receptors, Notch/metabolism
Signal Transduction/genetics
Zebrafish/embryology
Zebrafish/genetics*
Zebrafish/metabolism
Zebrafish Proteins/genetics*
Zebrafish Proteins/metabolism

(all 24)

PubMed

29473997 Full text @ FEBS J.

Abstract

The bone morphogenetic protein (BMP) signaling pathway plays a central role during vasculature development. Mutations or dysregulation of the BMP pathway members have been linked to arteriovenous malformations. In the present study, we investigated the effect of the BMP modulators BMPER and twisted gastrulation protein homolog 1 (TWSG1) on arteriovenous specification during zebrafish development and analyzed downstream Notch signaling pathway in human endothelial cells. Silencing of bmper and twsg1b in zebrafish embryos by morpholinos resulted in a pronounced enhancement of venous ephrinB4a marker expression and concomitant dysregulated arterial ephrinb2a marker expression detected by in situ hybridization. As arteriovenous specification was disturbed, we assessed the impact of BMPER and TWSG1 protein stimulation on the Notch signaling pathway on endothelial cells from different origin. Quantitative real-time PCR and western blot analysis showed increased expression of Notch target gene HES, HEY1/2 and EPHRINB2. Consistently, silencing of BMPER in endothelial cells by siRNAs decreased Notch signaling and downstream effectors. BMP receptor antagonist DMH1 abolished BMPER and BMP4 induced Notch signaling pathway activation. In conclusion, we found that in endothelial cells BMPER and TWSG1 are necessary for regular Notch signaling activity and in zebrafish embryos BMPER and TWSG1 preserve arteriovenous specification to prevent malformations. This article is protected by copyright. All rights reserved.

Genes / Markers

Marker	Marker Type	Name
bmper	GENE	BMP binding endothelial regulator
efnb2a	GENE	ephrin-B2a
ephb4a	GENE	eph receptor B4a
hey2	GENE	hes-related family bHLH transcription factor with YRPW motif 2
twsg1b	GENE	twisted gastrulation BMP signaling modulator 1b

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Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
efnb2a	y1Tg	chemical treatment by environment: DMH1	Long-pec	caudal artery	ISH	Fig. 6
efnb2a	y1Tg	control	Long-pec	caudal artery	ISH	Fig. 6
efnb2a	y1Tg	control	Long-pec	caudal artery	ISH	Fig. 1
efnb2a	y1Tg	chemical treatment by environment: DMH1	Long-pec	caudal vein plexus	ISH	Fig. 6
efnb2a	y1Tg	control	Long-pec	intersegmental vessel	ISH	Fig. 6
efnb2a	y1Tg	control	Long-pec	intersegmental vessel	ISH	Fig. 1
efnb2a	y1Tg + MO1-hey2	standard conditions	Long-pec	caudal artery	ISH	Fig. 1
efnb2a	y1Tg + MO1-twsg1b	standard conditions	Long-pec	caudal artery	ISH	Fig. 1
efnb2a	y1Tg + MO1-twsg1b	standard conditions	Long-pec	caudal vein plexus	ISH	Fig. 1
efnb2a	y1Tg + MO1-twsg1b + MO3-bmper	standard conditions	Long-pec	caudal artery	ISH	Fig. 1

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
y1Tg	chemical treatment by environment: DMH1	Long-pec	caudal vein plexus efnb2a expression increased amount, abnormal	Fig. 6
y1Tg	chemical treatment by environment: DMH1	Long-pec	caudal vein plexus efnb2a expression increased distribution, abnormal	Fig. 6
y1Tg	chemical treatment by environment: DMH1	Long-pec	caudal vein plexus efnb2a expression mislocalised, abnormal	Fig. 6
y1Tg	chemical treatment by environment: DMH1	Long-pec	caudal vein plexus ephb4a expression increased amount, abnormal	Fig. 6
y1Tg	chemical treatment by environment: DMH1	Long-pec	caudal vein plexus ephb4a expression increased distribution, abnormal	Fig. 6
y1Tg	chemical treatment by environment: DMH1	Long-pec	caudal vein plexus dilated, abnormal	Fig. 6
y1Tg + MO1-hey2	standard conditions	Long-pec	caudal artery efnb2a expression decreased amount, abnormal	Fig. 1
y1Tg + MO1-hey2	standard conditions	Long-pec	caudal artery efnb2a expression decreased distribution, abnormal	Fig. 1
y1Tg + MO1-hey2	standard conditions	Long-pec	caudal artery ephb4a expression increased distribution, abnormal	Fig. 2
y1Tg + MO1-hey2	standard conditions	Long-pec	caudal vein plexus ephb4a expression increased amount, abnormal	Fig. 2

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
y1Tg	Tg(fli1:EGFP)	Transgenic Insertion

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
bmper	MO3-bmper	MRPHLNO
hey2	MO1-hey2	MRPHLNO
twsg1b	MO1-twsg1b	MRPHLNO

Fish

Fish
y1Tg
y1Tg + MO1-hey2
y1Tg + MO1-twsg1b
y1Tg + MO1-twsg1b + MO3-bmper
y1Tg + MO3-bmper

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP

Mapping

Esser et al., 2018 ZDB-PUB-180224-5 PMID:29473997

Extracellular bone morphogenetic protein modulator BMPER and twisted gastrulation homolog 1 preserve arterial venous specification in zebrafish blood vessel development and regulate Notch signaling in endothelial cells

Esser et al., 2018

ZDB-PUB-180224-5
PMID:29473997