PUBLICATION

Neuropilin 1 mediates epicardial activation and revascularization in the regenerating zebrafish heart

Authors

Lowe, V., Wisniewski, L., Sayers, J., Evans, I., Frankel, P., Mercader-Huber, N., Zachary, I.C., Pellet-Many, C.

ID

ZDB-PUB-190608-1

Date

2019

Source

Development (Cambridge, England) 146(13): (Journal)

Registered Authors

Keywords

Epicardium, Heart, Neuropilin, Regeneration, Zebrafish

MeSH Terms

Heart/physiology*
Zebrafish/physiology
Coronary Vessels/physiology
Cold Temperature
Animals, Genetically Modified
Cells, Cultured
Rats
Animals
Cell Movement/genetics
Neovascularization, Physiologic/genetics*
Neuropilin-1/genetics
Neuropilin-1/physiology*
Pericardium/physiology*
Myocytes, Cardiac/physiology
Heart Injuries/etiology
Heart Injuries/pathology
Heart Injuries/physiopathology
Regeneration/genetics*

(all 18)

PubMed

31167777 Full text @ Development

Abstract

Unlike adult mammals, zebrafish can regenerate their heart. A key mechanism for regeneration is the activation of the epicardium, leading to the establishment of a supporting scaffold for new cardiomyocytes, angiogenesis and cytokine secretion. Neuropilins are co-receptors mediating signaling of kinase receptors for cytokines known to play critical roles in zebrafish heart regeneration. We investigated the role of neuropilins in response to cardiac injury and heart regeneration. All four neuropilin isoforms nrp1a, nrp1b, nrp2a and nrp2b were upregulated by the activated epicardium and a nrp1a knockout mutant showed a significant delay in heart regeneration and displayed persistent collagen deposition. The regenerating hearts of nrp1a mutants were less vascularized and epicardial-derived cell migration and re-expression of the developmental gene wt1b was impaired. Moreover, cryoinjury-induced activation and migration of epicardial cells in heart explants was reduced in nrp1a mutant. These results identify a key role for Nrp1 in zebrafish heart regeneration, mediated through epicardial activation, migration and revascularization.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Qualifier	Anatomy	Assay	Figure
EGFP	li1Tg	control	Adult	Not Detected	cardiac ventricle	IHC	Fig. 2
EGFP	li1Tg	cold damage: cardiac ventricle	Adult		regenerating tissue ventricular epicardium	IHC	Fig. 2
EGFP	li1Tg	cold damage: cardiac ventricle	Adult		regenerating tissue ventricular epicardium	IHC	Fig. 6
EGFP	nrp1a^{sa1485/sa1485}; li1Tg	cold damage: cardiac ventricle	Adult		regenerating tissue ventricular epicardium	IHC	Fig. 6
EGFP	y1Tg	control	Adult		heart vasculature	IHC	Fig. 2
EGFP	y1Tg	cold damage: cardiac ventricle	Adult		heart vasculature	IHC	Fig. 2
EGFP	y1Tg	cold damage: cardiac ventricle	Adult		regenerating tissue heart vasculature	IHC	Fig. 2
nrp1a	AB/TL	cold damage: cardiac ventricle	Adult		cardiac ventricle	RTPCR	Fig. 1
nrp1a	AB/TL	control	Long-pec		fin bud	ISH	Fig. S2
nrp1a	AB/TL	control	Long-pec		otic vesicle	ISH	Fig. S2

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB/TL	cold damage: cardiac ventricle	Adult	cardiac ventricle nrp1a expression increased amount, abnormal	Fig. 1
AB/TL	cold damage: cardiac ventricle	Adult	cardiac ventricle nrp1b expression increased amount, abnormal	Fig. 1
AB/TL	cold damage: cardiac ventricle	Adult	cardiac ventricle nrp2a expression increased amount, abnormal	Fig. 1
AB/TL	cold damage: cardiac ventricle	Adult	cardiac ventricle pdgfab expression increased amount, abnormal	Fig. S1
AB/TL	cold damage: cardiac ventricle	Adult	cardiac ventricle pdgfrb expression increased amount, abnormal	Fig. S1
AB/TL	cold damage: cardiac ventricle	Adult	cardiac ventricle tgfb1a expression increased amount, abnormal	Fig. S1
AB/TL	cold damage: cardiac ventricle	Adult	cardiac ventricle vegfc expression increased amount, abnormal	Fig. S1
AB/TL	cold damage: cardiac ventricle	Adult	cardiac ventricle ab1-nrp1 labeling increased amount, abnormal	Fig. 1
AB/TL	cold damage: cardiac ventricle	Adult	ventricular epicardium nrp1a expression increased amount, abnormal	Fig. 1
AB/TL	cold damage: cardiac ventricle	Adult	ventricular epicardium nrp1b expression increased amount, abnormal	Fig. 1

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
li1Tg	Tg(wt1b:EGFP)	Transgenic Insertion
s896Tg	Tg(kdrl:Hsa.HRAS-mCherry)	Transgenic Insertion
sa1485		Point Mutation	nrp1a
y1Tg	Tg(fli1:EGFP)	Transgenic Insertion

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Human Disease / Model

Sequence Targeting Reagents

Fish

Fish
AB/TL
li1Tg
nrp1a^{sa1485/sa1485}
nrp1a^{sa1485/sa1485}; li1Tg
nrp1a^{sa1485/sa1485}; y1Tg
y1Tg

Antibodies

Name	Type	Antigen Genes	Isotypes	Host Organism
Ab1-actb	monoclonal		IgG1	Mouse
Ab1-aldh1a2	polyclonal	aldh1a2	IgG	Rabbit
Ab1-nrp1	monoclonal		IgG	Rabbit
Ab1-wt1	monoclonal		IgG1	Mouse
Ab2-aldh2	polyclonal		IgG	Rabbit
Ab2-ctnnb1	polyclonal	ctnnb1		Rabbit
Ab2-pcna	monoclonal	pcna	IgG2a	Mouse
Ab4-mef2c	polyclonal		IgG	Rabbit
Ab4-tpm	monoclonal		IgG1	Mouse
Ab5-gapdh	polyclonal		IgG	Goat

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Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP
mCherry	EFG	mCherry

Mapping

Lowe et al., 2019 ZDB-PUB-190608-1 PMID:31167777

Neuropilin 1 mediates epicardial activation and revascularization in the regenerating zebrafish heart

Lowe et al., 2019

ZDB-PUB-190608-1
PMID:31167777