PUBLICATION

Vegfd modulates both angiogenesis and lymphangiogenesis during zebrafish embryonic development

Authors

Bower, N.I., Vogrin, A.J., Le Guen, L., Chen, H., Stacker, S.A., Achen, M.G., Hogan, B.M.

ID

ZDB-PUB-170115-4

Date

2017

Source

Development (Cambridge, England) 144(3): 507-518 (Journal)

Registered Authors

Hogan, Ben M., Le Guen, Ludovic

Keywords

Flt4, Kdr, Lymphangiogenesis, Lymphatic, Vegfc, Vegfd

MeSH Terms

Signal Transduction
Zebrafish/embryology*
Zebrafish/genetics
Zebrafish/physiology*
Lymphangiogenesis/genetics
Lymphangiogenesis/physiology*
Animals
Vascular Endothelial Growth Factor C/genetics
Vascular Endothelial Growth Factor C/physiology
Intracellular Signaling Peptides and Proteins/genetics
Intracellular Signaling Peptides and Proteins/physiology
Vascular Endothelial Growth Factor Receptor-2/genetics
Vascular Endothelial Growth Factor Receptor-2/physiology
Models, Biological
Vascular Endothelial Growth Factor Receptor-1/genetics
Vascular Endothelial Growth Factor Receptor-1/physiology
Mutagenesis
Neovascularization, Physiologic/genetics
Neovascularization, Physiologic/physiology*
Zebrafish Proteins/genetics
Zebrafish Proteins/physiology*
Sequence Deletion
Up-Regulation
Vascular Endothelial Growth Factor D/genetics
Vascular Endothelial Growth Factor D/physiology*
Membrane Proteins/genetics
Membrane Proteins/physiology

(all 27)

PubMed

28087639 Full text @ Development

Abstract

Vascular endothelial growth factors (VEGFs) control angiogenesis and lymphangiogenesis during development and in pathological conditions. In the zebrafish trunk, Vegfa controls the formation of intersegmental arteries by primary angiogenesis and Vegfc is essential for secondary angiogenesis, the formation of veins and lymphatics. VEGFD has been largely thought of as dispensable for vascular development in vertebrates. Here, we generated a zebrafish vegfd mutant by genome editing. vegfd mutants display significant defects in facial lymphangiogenesis independent of vegfc function. Strikingly, we find that vegfc and vegfd cooperatively control lymphangiogenesis throughout the embryo, including during the formation of the trunk lymphatic vasculature. Interestingly, we find that vegfd and vegfc also redundantly drive artery hyperbranching phenotypes observed upon depletion of Flt1 or Dll4. Epistasis and biochemical binding assays suggest that during primary angiogenesis Vegfd influences these phenotypes through Kdr (Vegfr2) rather than Flt4 (Vegfr3). These data demonstrate that, rather than being dispensable during development, Vegfd plays context specific indispensible and also compensatory roles during both blood vessel angiogenesis and lymphangiogenesis.

Genes / Markers

Marker	Marker Type	Name
ccbe1	GENE	collagen and calcium binding EGF domains 1
dll4	GENE	delta-like 4 (Drosophila)
flt1	GENE	fms related receptor tyrosine kinase 1
flt4	GENE	fms related receptor tyrosine kinase 4
kdr	GENE	kinase insert domain receptor (a type III receptor tyrosine kinase)
kdrl	GENE	kinase insert domain receptor like
rpl13	GENE	ribosomal protein L13
rps29	GENE	ribosomal protein S29
vegfaa	GENE	vascular endothelial growth factor Aa
vegfab	GENE	vascular endothelial growth factor Ab

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Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
DsRed	flt4^hu4602/+; nz101Tg	standard conditions	Days 7-13	lymph vasculature	IFL	Fig. 3
DsRed	flt4^hu4602/+; nz101Tg	standard conditions	Days 7-13	thoracic duct	IFL	Fig. 3
DsRed	flt4^hu4602/+; vegfd^uq9bh/uq9bh; nz101Tg	standard conditions	Days 7-13	lymph vasculature	IFL	Fig. 3
DsRed	flt4^hu4602/+; vegfd^uq9bh/uq9bh; nz101Tg	standard conditions	Days 7-13	thoracic duct	IFL	Fig. 3
DsRed	nz101Tg; y7Tg	standard conditions	Day 5	cranial lymph vessel	IFL	Fig. 1
DsRed	nz101Tg; y7Tg	standard conditions	Day 5	lateral facial lymph vessel	IFL	Fig. 1
DsRed	nz101Tg; y7Tg	standard conditions	Day 5	medial facial lymph vessel	IFL	Fig. 1
DsRed	nz101Tg; y7Tg	standard conditions	Day 5	otolithic lymph vessel	IFL	Fig. 1
DsRed	vegfc^{hu5055/hu5055}; nz101Tg; y7Tg	standard conditions	Day 5	cranial lymph vessel	IFL	Fig. 1
DsRed	vegfc^{hu5055/hu5055}; nz101Tg; y7Tg	standard conditions	Day 5	lateral facial lymph vessel	IFL	Fig. 1

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
dll4^uq10bh/+; y1Tg	standard conditions	Protruding-mouth	intersegmental artery branchiness, normal	Fig. 6
dll4^uq10bh/+; y1Tg + MO3-flt1	standard conditions	Protruding-mouth	intersegmental artery increased branchiness, exacerbated	Fig. 6
flt4^hu4602/+; vegfd^uq9bh/uq9bh; nz101Tg	standard conditions	Days 7-13	thoracic duct decreased amount, abnormal	Fig. 3
flt4^hu4602/+; vegfd^uq9bh/uq9bh; nz101Tg	standard conditions	Days 7-13	thoracic duct lymph vessel development decreased occurrence, abnormal	Fig. 3
vegfc^hu5055/+; vegfd^uq9bh/+; nz101Tg; y7Tg	standard conditions	Day 5	facial lymphatic vessel lymphangiogenesis decreased occurrence, abnormal	Fig. 1
vegfc^hu5055/+; vegfd^uq9bh/+; nz101Tg; y7Tg	standard conditions	Day 5	lateral facial lymph vessel endothelial cell decreased amount, abnormal	Fig. 1
vegfc^hu5055/+; vegfd^uq9bh/+; nz101Tg; y7Tg	standard conditions	Day 5	medial facial lymph vessel endothelial cell decreased amount, abnormal	Fig. 1
vegfc^hu5055/+; vegfd^uq9bh/+; y1Tg	standard conditions	Long-pec	lymphangioblast cord decreased amount, abnormal	Fig. 2
vegfc^hu5055/+; vegfd^uq9bh/+; y1Tg	standard conditions	Long-pec	lymphangioblast cord lymph vessel development decreased occurrence, abnormal	Fig. 2
vegfc^hu5055/+; vegfd^uq9bh/uq9bh; nz101Tg; y7Tg	standard conditions	Day 5	medial facial lymph vessel endothelial cell decreased amount, exacerbated	Fig. 1

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
hu3613		Point Mutation	ccbe1
hu4602		Point Mutation	flt4
hu4624Tg	TgBAC(flt1:Citrine)	Transgenic Insertion
hu5055		Point Mutation	vegfc
nz101Tg	Tg(-5.2lyve1b:DsRed)	Transgenic Insertion
uq9bh		Small Deletion	vegfd
uq10bh		Small Deletion	dll4
y1Tg	Tg(fli1:EGFP)	Transgenic Insertion
y7Tg	Tg(fli1:nEGFP)	Transgenic Insertion

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Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
dll4	MO4-dll4	MRPHLNO
dll4	TALEN1-dll4	TALEN
flt1	MO3-flt1	MRPHLNO
flt4	MO3-flt4	MRPHLNO
kdr	MO1-kdr	MRPHLNO
kdrl	MO4-kdrl	MRPHLNO
vegfd	TALEN1-vegfd	TALEN

Fish

Fish
dll4^uq10bh/+; y1Tg
dll4^uq10bh/+; y1Tg + MO3-flt1
flt4^hu4602/+; nz101Tg
flt4^hu4602/+; vegfd^uq9bh/uq9bh; nz101Tg
hu4624Tg; nz101Tg
nz101Tg; y7Tg
vegfc^{hu5055/hu5055}; nz101Tg; y7Tg
vegfc^{hu5055/hu5055}; vegfd^uq9bh/+; nz101Tg; y7Tg
vegfc^{hu5055/hu5055}; vegfd^uq9bh/+; y1Tg
vegfc^{hu5055/hu5055}; vegfd^uq9bh/uq9bh; nz101Tg; y7Tg

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Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
DsRed	EFG	DsRed
EGFP	EFG	EGFP
YFP	EFG	YFP

Mapping

Bower et al., 2017 ZDB-PUB-170115-4 PMID:28087639

Vegfd modulates both angiogenesis and lymphangiogenesis during zebrafish embryonic development

Bower et al., 2017

ZDB-PUB-170115-4
PMID:28087639