PUBLICATION

Regulation of cardiomyocyte behavior in zebrafish trabeculation by Neuregulin 2a signaling

Authors

Rasouli, S.J., Stainier, D.Y.R.

ID

ZDB-PUB-170510-5

Date

2017

Source

Nature communications 8: 15281 (Journal)

Registered Authors

Stainier, Didier

Keywords

Cell proliferation, Cell signalling, Development, Super-resolution microscopy

MeSH Terms

Embryo, Nonmammalian/metabolism
Myocytes, Cardiac/metabolism*
Heart Ventricles/embryology
Heart Ventricles/metabolism
Heart Atria/cytology
Heart Atria/embryology
Recombinant Fusion Proteins/metabolism
Coronary Circulation
Zebrafish Proteins/metabolism*
Larva/growth & development
Larva/metabolism
Mutation/genetics
Zebrafish/embryology
Zebrafish/metabolism*
Signal Transduction*
Organogenesis*
Animals
Animals, Genetically Modified

(all 18)

PubMed

28485381 Full text @ Nat. Commun.

Abstract

Trabeculation is crucial for cardiac muscle growth in vertebrates. This process requires the Erbb2/4 ligand Neuregulin (Nrg), secreted by the endocardium, as well as blood flow/cardiac contractility. Here, we address two fundamental, yet unresolved, questions about cardiac trabeculation: why does it initially occur in the ventricle and not the atrium, and how is it modulated by blood flow/contractility. Using loss-of-function approaches, we first show that zebrafish Nrg2a is required for trabeculation, and using a protein-trap line, find that it is expressed in both cardiac chambers albeit with different spatiotemporal patterns. Through gain-of-function experiments, we show that atrial cardiomyocytes can also respond to Nrg2a signalling, suggesting that the cardiac jelly, which remains prominent in the atrium, represents a barrier to Erbb2/4 activation. Furthermore, we find that blood flow/contractility is required for Nrg2a expression, and that while non-contractile hearts fail to trabeculate, non-contractile cardiomyocytes are also competent to respond to Nrg2a/Erbb2 signalling.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
EGFP	bns140Tg; s883Tg	standard conditions	Long-pec	atrial myocardium membrane	IFL	Fig. 5
EGFP	bns140Tg; s883Tg	standard conditions	Protruding-mouth	atrial myocardium membrane	IFL	Fig. 5
EGFP	bns140Tg; s883Tg	standard conditions	Day 6	atrial myocardium membrane	IFL	Fig. 5
EGFP	bns140Tg; s883Tg	standard conditions	Day 5	atrial myocardium membrane	IFL	Fig. 5
EGFP	bns140Tg; s883Tg	standard conditions	Long-pec	myocardium membrane	IFL	Fig. 5
EGFP	bns140Tg; s883Tg	standard conditions	Day 6	myocardium membrane	IFL	Fig. 5
EGFP	bns140Tg; s883Tg	standard conditions	Day 5	myocardium membrane	IFL	Fig. 5
EGFP	bns140Tg; s883Tg	standard conditions	Protruding-mouth	myocardium membrane	IFL	Fig. 5
EGFP	bns140Tg; s883Tg	control	Day 5	myocardium	IFL	Fig. S8
EGFP	bns140Tg; s883Tg	chemical treatment: PD 168393	Day 5	myocardium	IFL	Fig. S8

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
bns140Tg; ncv43Tg	control	Protruding-mouth	atrial myocardium cardiac muscle cell proliferation increased occurrence, abnormal	Fig. S9
bns140Tg; ncv43Tg	control	Protruding-mouth	ventricular myocardium cardiac muscle cell proliferation increased occurrence, abnormal	Fig. S9
bns140Tg; ncv43Tg	control	Day 4	atrial myocardium cardiac muscle cell proliferation increased occurrence, abnormal	Fig. S9
bns140Tg; ncv43Tg	control	Day 4	ventricular myocardium cardiac muscle cell proliferation increased occurrence, abnormal	Fig. S9
bns140Tg; s883Tg	control	Day 5	ventricular myocardium cardiac muscle cell increased amount, abnormal	Fig. S8
bns140Tg; s883Tg	standard conditions	Long-pec	atrial myocardium cardiac muscle cell increased amount, abnormal	Fig. 5
bns140Tg; s883Tg	standard conditions	Long-pec	ventricular myocardium cardiac muscle cell increased amount, abnormal	Fig. 5
bns140Tg; s883Tg	standard conditions	Protruding-mouth	atrial myocardium cardiac muscle cell increased amount, abnormal	Fig. 5
bns140Tg; s883Tg	standard conditions	Protruding-mouth	ventricular myocardium cardiac muscle cell increased amount, abnormal	Fig. 5
bns140Tg; s883Tg	standard conditions	Day 5	atrial myocardium cardiac muscle cell increased amount, abnormal	Fig. 5

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
bns101		Small Deletion	nrg1
bns140Tg	Tg(myl7:nrg2a-2A-Tomato)	Transgenic Insertion
bns199Tg	Tg(fli1:nrg2a-2A-Tomato)	Transgenic Insertion
mn0237Gt	Gt(GBT-rp2)	Transgenic Insertion	nrg2a
ncv43Tg	Tg(myl7:mVenus-gmnn)	Transgenic Insertion
s883Tg	Tg(myl7:EGFP-Hsa.HRAS)	Transgenic Insertion
s896Tg	Tg(kdrl:Hsa.HRAS-mCherry)	Transgenic Insertion
s974Tg	Tg(myl7:LIFEACT-GFP)	Transgenic Insertion
st61		Point Mutation	erbb2
ubs1Tg	Tg(kdrl:NLS-EGFP)	Transgenic Insertion

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Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
nrg1	TALEN1-nrg1	TALEN
tnnt2a	MO1-tnnt2a	MRPHLNO

Fish

Fish
bns140Tg; ncv43Tg
bns140Tg; s883Tg
bns140Tg; s883Tg + MO1-tnnt2a
ncv43Tg
nrg1^{bns101/bns101}; s974Tg
nrg2a^{mn0237Gt/mn0237Gt}
nrg2a^{mn0237Gt/mn0237Gt}; s974Tg
nrg2a^mn0237Gt/+; s974Tg
nrg2a^mn0237Gt/+; ubs1Tg
nrg2a^mn0237Gt/+; ubs1Tg + MO1-tnnt2a

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Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
ECFP	EFG	ECFP
EGFP	EFG	EGFP
GFP	EFG	GFP
mCherry	EFG	mCherry
mRFP1	EFG	mRFP1
Tomato	EFG	Tomato
Venus	EFG	Venus

Mapping

Rasouli et al., 2017 ZDB-PUB-170510-5 PMID:28485381

Regulation of cardiomyocyte behavior in zebrafish trabeculation by Neuregulin 2a signaling

Rasouli et al., 2017

ZDB-PUB-170510-5
PMID:28485381