PUBLICATION

Tmem2 Regulates Embryonic Vegf Signaling by Controlling Hyaluronic Acid Turnover

Authors

De Angelis, J.E., Lagendijk, A.K., Chen, H., Tromp, A., Bower, N.I., Tunny, K.A., Brooks, A.J., Bakkers, J., Francois, M., Yap, A.S., Simons, C., Wicking, C., Hogan, B.M., Smith, K.A.

ID

ZDB-PUB-170125-2

Date

2017

Source

Developmental Cell 40: 123-136 (Journal)

Registered Authors

Bakkers, Jeroen, Hogan, Ben M., Smith, Kelly

Keywords

VEGF, angiogenesis, extracellular matrix, hyaluronic acid, tmem2, zebrafish

MeSH Terms

Veins/metabolism
Endothelial Cells/metabolism
Zebrafish Proteins/chemistry
Zebrafish Proteins/metabolism*
Phenotype
Torso/blood supply
Mutation/genetics
Embryo, Nonmammalian/metabolism*
Signal Transduction*
Arteries/metabolism
Membrane Proteins/chemistry
Membrane Proteins/metabolism*
Neovascularization, Physiologic
Polymerization
Vascular Endothelial Growth Factor A/metabolism*
Hyaluronic Acid/metabolism*
Zebrafish/embryology*
Zebrafish/metabolism*
Animals

(all 19)

PubMed

28118600 Full text @ Dev. Cell

Abstract

Angiogenesis is responsible for tissue vascularization during development, as well as in pathological contexts, including cancer and ischemia. Vascular endothelial growth factors (VEGFs) regulate angiogenesis by acting through VEGF receptors to induce endothelial cell signaling. VEGF is processed in the extracellular matrix (ECM), but the complexity of ECM control of VEGF signaling and angiogenesis remains far from understood. In a forward genetic screen, we identified angiogenesis defects in tmem2 zebrafish mutants that lack both arterial and venous Vegf/Vegfr/Erk signaling. Strikingly, tmem2 mutants display increased hyaluronic acid (HA) surrounding developing vessels. Angiogenesis in tmem2 mutants was rescued, or restored after failed sprouting, by degrading this increased HA. Furthermore, oligomerized HA or overexpression of Vegfc rescued angiogenesis in tmem2 mutants. Based on these data, and the known structure of Tmem2, we find that Tmem2 regulates HA turnover to promote normal Vegf signaling during developmental angiogenesis.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
cemip2	WT	standard conditions	Prim-15	angiogenic sprout	ISH	Fig. 2
cemip2	WT	standard conditions	Prim-15	caudal vein plexus	ISH	Fig. 2
cemip2	WT	standard conditions	Prim-15	posterior cardinal vein endothelial cell	ISH	Fig. 2
cemip2	WT	standard conditions	Prim-5	whole organism	ISH	Fig. 2
EGFP	cemip2^{hu5935/hu5935}; kca4Tg; s843Tg; uq2bhTg	heat shock	Prim-25	trunk vasculature	IFL	Fig. 7
EGFP	cemip2^{hu5935/hu5935}; s843Tg	standard conditions	26+ somites	dorsal aorta endothelial cell	IHC	Fig. 5
EGFP	cemip2^{hu5935/hu5935}; s843Tg	standard conditions	26+ somites	dorsal aorta endothelial cell	IHC	Fig. 1
EGFP	cemip2^{hu5935/hu5935}; s843Tg	standard conditions	Prim-15	dorsal aorta endothelial cell	IHC	Fig. 1
EGFP	cemip2^{hu5935/hu5935}; s843Tg	standard conditions	Prim-5	dorsal aorta endothelial cell	IHC	Fig. 3
EGFP	cemip2^{hu5935/hu5935}; s843Tg	control	Prim-5	intersegmental vessel	IFL	Fig. 6

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	chemical treatment by environment: semaxanib	Prim-25	intersegmental vessel decreased amount, abnormal	Fig. 5
WT + MO1-kdr + MO4-kdrl	standard conditions	Prim-25	intersegmental vessel decreased amount, abnormal	Fig. 5
WT + MO2-vegfaa	standard conditions	Prim-25	intersegmental vessel decreased amount, abnormal	Fig. 5
cemip2^{hu5935/hu5935}	control	Prim-25	intersegmental vessel decreased amount, abnormal	Fig. 7
cemip2^{hu5935/hu5935}	standard conditions	Long-pec	dorsal aorta hyaluronic acid increased amount, abnormal	Fig. 3
cemip2^{hu5935/hu5935}	standard conditions	Long-pec	intersegmental vessel decreased amount, abnormal	Fig. 2
cemip2^{hu5935/hu5935}	standard conditions	Long-pec	intersegmental vessel sprouting angiogenesis decreased occurrence, abnormal	Fig. 2
cemip2^{hu5935/hu5935}	standard conditions	Long-pec	posterior cardinal vein hyaluronic acid increased amount, abnormal	Fig. 3
cemip2^{hu5935/hu5935}	chemical treatment by environment: semaxanib	Prim-25	intersegmental vessel decreased amount, abnormal	Fig. 7
cemip2^{hu5935/hu5935}; kca4Tg; s843Tg; uq2bhTg	heat shock	Prim-25	intersegmental vessel amount, ameliorated	Fig. 7

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
fr14Tg	Tg(hsp70l:nog3)	Transgenic Insertion
hu4624Tg	TgBAC(flt1:Citrine)	Transgenic Insertion
hu4800		Point Mutation	cemip2
hu5935		Point Mutation	cemip2
kca4Tg	Tg(-1.5hsp70l:GAL4)	Transgenic Insertion
nz101Tg	Tg(-5.2lyve1b:DsRed)	Transgenic Insertion
s843Tg	Tg(kdrl:EGFP)	Transgenic Insertion
s916Tg	Tg(kdrl:Hsa.HRAS-mCherry)	Transgenic Insertion
sd15Tg	Tg(UAS:cemip2-EGFP)	Transgenic Insertion
ubs4Tg	Tg(fli1:GAL4FF)	Transgenic Insertion

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Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
kdr	MO1-kdr	MRPHLNO
kdrl	MO4-kdrl	MRPHLNO
vegfaa	MO2-vegfaa	MRPHLNO

Fish

Fish
cemip2^{hu5935/hu5935}
cemip2^{hu5935/hu5935}; kca4Tg; s843Tg; uq2bhTg
cemip2^{hu5935/hu5935}; s843Tg
cemip2^{hu5935/hu5935}; s916Tg
cemip2^{hu5935/hu5935}; y1Tg
kca4Tg; s843Tg; uq2bhTg
s843Tg
s916Tg
uq3ksTg; y1Tg
WT

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Antibodies

Name	Type	Antigen Genes	Isotypes	Host Organism
Ab9-mapk	monoclonal		IgG	Rabbit

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
DsRed	EFG	DsRed
EGFP	EFG	EGFP
GAL4	EFG	GAL4
GAL4FF	EFG	GAL4FF
GFP	EFG	GFP
mCherry	EFG	mCherry
YFP	EFG	YFP

Mapping

De Angelis et al., 2017 ZDB-PUB-170125-2 PMID:28118600

Tmem2 Regulates Embryonic Vegf Signaling by Controlling Hyaluronic Acid Turnover

De Angelis et al., 2017

ZDB-PUB-170125-2
PMID:28118600