PUBLICATION

Heparan Sulfate Proteoglycans Regulate Fgf Signaling and Cell Polarity during Collective Cell Migration

Authors: Venero Galanternik, M., Kramer, K.L., Piotrowski, T.
ID: ZDB-PUB-160713-12
Date: 2015
Source: Cell Reports 10(30): 414-428 (Journal)
Registered Authors: Kramer, Kenneth, Piotrowski, Tatjana, Venero Galanternik, Marina
Keywords: none
MeSH Terms: none
PubMed: 25600875 Full text @ Cell Rep.

Abstract

Collective cell migration is a highly regulated morphogenetic movement during embryonic development and cancer invasion that involves the precise orchestration and integration of cell-autonomous mechanisms and environmental signals. Coordinated lateral line primordium migration is controlled by the regulation of chemokine receptors via compartmentalized Wnt/β-catenin and fibroblast growth factor (Fgf) signaling. Analysis of mutations in two exostosin glycosyltransferase genes (extl3 and ext2) revealed that loss of heparan sulfate (HS) chains results in a failure of collective cell migration due to enhanced Fgf ligand diffusion and loss of Fgf signal transduction. Consequently, Wnt/β-catenin signaling is activated ectopically, resulting in the subsequent loss of the chemokine receptor cxcr7b. Disruption of HS proteoglycan (HSPG) function induces extensive, random filopodia formation, demonstrating that HSPGs are involved in maintaining cell polarity in collectively migrating cells. The HSPGs themselves are regulated by the Wnt/β-catenin and Fgf pathways and thus are integral components of the regulatory network that coordinates collective cell migration with organ specification and morphogenesis.

Genes / Markers

Marker	Marker Type	Name
ackr3b	GENE	atypical chemokine receptor 3b
apc	GENE	APC regulator of WNT signaling pathway
atoh1a	GENE	atonal bHLH transcription factor 1a
axin2	GENE	axin 2 (conductin, axil)
cxcl12a	GENE	chemokine (C-X-C motif) ligand 12a (stromal cell-derived factor 1)
cxcr4b	GENE	chemokine (C-X-C motif), receptor 4b
dkk1b	GENE	dickkopf WNT signaling pathway inhibitor 1b
etv4	GENE	ETS variant transcription factor 4
ext2	GENE	exostosin glycosyltransferase 2
extl3	GENE	exostosin-like glycosyltransferase 3

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Figures

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Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	chemical treatment by environment: SU5402	Prim-15	posterior lateral line primordium gpc1b expression increased distribution, abnormal	Fig. 1
WT	chemical treatment by environment: SU5402	Prim-15	posterior lateral line primordium gpc4 expression decreased distribution, abnormal	Fig. 1
WT	chemical treatment by environment: SU5402	Prim-15	posterior lateral line primordium lef1 expression increased distribution, abnormal	Fig. 3
WT	chemical treatment by environment: SU5402	Prim-15	posterior lateral line primordium sdc3 expression spatial pattern, abnormal	Fig. 1
WT	chemical treatment by environment: SU5402	Prim-15	posterior lateral line primordium sdc4 expression absent, abnormal	Fig. 1
WT	heat shock, chemical treatment by environment: sodium chlorate	High-pec	posterior lateral line primordium dkk1b expression decreased distribution, abnormal	Fig. 4
WT	heat shock, chemical treatment by environment: sodium chlorate	High-pec	posterior lateral line primordium etv4 expression decreased distribution, abnormal	Fig. 4
WT	heat shock, chemical treatment by environment: sodium chlorate	High-pec	posterior lateral line primordium fgf3 expression increased distribution, abnormal	Fig. 4
WT	heat shock, chemical treatment by environment: sodium chlorate	High-pec	posterior lateral line primordium lef1 expression increased distribution, abnormal	Fig. 4
apc^hu745/hu745	standard conditions	Prim-15	posterior lateral line primordium gpc1b expression increased distribution, abnormal	Fig. 1

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
hu745		Point Mutation	apc
kyu1Tg	Tg(OTM:d2EGFP)	Transgenic Insertion
pd3Tg	Tg(hsp70l:Xla.Fgfr1,cryaa:DsRed)	Transgenic Insertion
tm70g		Point Mutation	extl3
to79c		Point Mutation	ext2
w32Tg	Tg(hsp70l:dkk1b-GFP)	Transgenic Insertion
zf51Tg	Tg(hsp70l:cxcl12a)	Transgenic Insertion
zf106Tg	Tg(-8.0cldnb:LY-EGFP)	Transgenic Insertion

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Human Disease / Model

Sequence Targeting Reagents

Fish

Fish
apc^hu745/hu745
ext2^to79c/to79c
ext2^to79c/to79c; extl3^tm70g/tm70g
ext2^to79c/to79c; extl3^tm70g/tm70g; zf106Tg
ext2^to79c/to79c; zf106Tg
extl3^tm70g/tm70g; zf106Tg
kyu1Tg
pd3Tg
w32Tg
WT

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
d2EGFP	EFG	d2EGFP
DsRed	EFG	DsRed
EGFP	EFG	EGFP
GFP	EFG	GFP

Mapping

Venero Galanternik et al., 2015 ZDB-PUB-160713-12 PMID:25600875

Heparan Sulfate Proteoglycans Regulate Fgf Signaling and Cell Polarity during Collective Cell Migration

Venero Galanternik et al., 2015

ZDB-PUB-160713-12
PMID:25600875