PUBLICATION

Glutathione peroxidase 4 inhibits Wnt/β-catenin signaling and regulates dorsal organizer formation in zebrafish embryos

Authors

Rong, X., Zhou, Y., Liu, Y., Zhao, B., Wang, B., Wang, C., Gong, X., Tang, P., Lu, L., Li, Y., Zhao, C., Zhou, J.

ID

ZDB-PUB-170318-5

Date

2017

Source

Development (Cambridge, England) 144(9): 1687-1697 (Journal)

Registered Authors

Liu, Yunzhang, Rong, Xiaozhi, Wang, Bo, Wang, Caixia, Zhao, Chengtian, Zhou, Jianfeng

Keywords

Glutathione peroxidase 4, Tcf/Lef, Wnt/β-catenin signaling, dorsal organizer, zebrafish

MeSH Terms

Animals
Zebrafish/embryology*
Zebrafish/metabolism*
Humans
Amino Acid Sequence
HEK293 Cells
CRISPR-Cas Systems/genetics
Transcription, Genetic
Evolution, Molecular
Signal Transduction/genetics
Wnt Signaling Pathway*
Base Sequence
Organizers, Embryonic/enzymology*
Zygote/metabolism
Protein Binding/genetics
Glutathione Peroxidase/chemistry
Glutathione Peroxidase/deficiency
Glutathione Peroxidase/metabolism*
Embryo, Nonmammalian/cytology
Embryo, Nonmammalian/enzymology*
Zebrafish Proteins/chemistry
Zebrafish Proteins/genetics
Zebrafish Proteins/metabolism*
Selenium/metabolism
Phenotype
Gene Expression Regulation, Developmental
Promoter Regions, Genetic/genetics

(all 27)

PubMed

28302747 Full text @ Development

Abstract

The Wnt/β-catenin signaling pathway plays pivotal roles in axis formation during embryogenesis and in adult tissue homeostasis. Glutathione peroxidase 4 (GPX4) is a selenoenzyme and participates in the reduction of peroxides. Its synthesis depends on the availability of the element selenium. However, the roles of GPX4 in vertebrate embryonic development and underlying mechanisms are largely unknown. Here, we show that maternal loss of zebrafish gpx4b promotes embryonic dorsal organizer formation, whereas overexpression of gpx4b inhibits the development of the dorsal organizer. Depletion of human GPX4 and zebrafish gpx4b (GPX4/gpx4b) increases, while GPX4/gpx4b overexpression decreases, Wnt/β-catenin signaling in vivo and in vitro Functional and epistatic studies showed that GPX4 functions at the Tcf/Lef level, independently of selenocysteine activation. Mechanistically, GPX4 interacts with Tcf/Lefs and inhibits Wnt activity by preventing the binding of Tcf/Lefs to the promoters of Wnt target genes, resulting in inhibitory action in the presence of Wnt/β-catenin signaling. Our findings unravel GPX4 as a suppressor of Wnt/β-catenin signals, suggesting a possible relationship between the Wnt/β-catenin pathway and selenium via the association of Tcf/Lef family proteins with GPX4.

Genes / Markers

Figures

Show all Figures

Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
gpx4b^ouc1/ouc1	standard conditions	Dome	whole organism chrd expression increased amount, abnormal	Fig. 2
gpx4b^ouc1/ouc1	standard conditions	Dome	whole organism dharma expression increased amount, abnormal	Fig. 2
gpx4b^ouc1/ouc1	standard conditions	Dome	whole organism ndr1 expression increased amount, abnormal	Fig. 2
gpx4b^ouc1/ouc1	standard conditions	Dome	whole organism dorsal region chrd expression increased distribution, abnormal	Fig. 2
gpx4b^ouc1/ouc1	standard conditions	Dome	whole organism dorsal region gsc expression increased distribution, abnormal	Fig. 2
gpx4b^ouc1/ouc1	standard conditions	75%-epiboly	anatomical structure cdx4 expression increased amount, abnormal	Fig. 2
gpx4b^ouc1/ouc1	standard conditions	75%-epiboly	anatomical structure sp5l expression increased amount, abnormal	Fig. 2
gpx4b^ouc1/ouc1	standard conditions	75%-epiboly	whole organism axin2 expression increased amount, abnormal	Fig. 2
gpx4b^ouc1/ouc1	standard conditions	75%-epiboly	whole organism ccnd1 expression increased amount, abnormal	Fig. 2
gpx4b^ouc1/ouc1	standard conditions	75%-epiboly	whole organism cdx4 expression increased amount, abnormal	Fig. 2

1 - 10 of 23

Show

Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
ouc1		Small Deletion	gpx4b
ouc2		Small Deletion	gpx4b

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
gpx4b	CRISPR1-gpx4b	CRISPR

Fish

Fish
gpx4b^ouc1/ouc1
gpx4b^ouc1
gpx4b^ouc2/ouc2
gpx4b^ouc2
TU

Antibodies

Orthology

Gene	Orthology
gpx4a
gpx4b

Engineered Foreign Genes

Mapping

Rong et al., 2017 ZDB-PUB-170318-5 PMID:28302747

Glutathione peroxidase 4 inhibits Wnt/β-catenin signaling and regulates dorsal organizer formation in zebrafish embryos

Rong et al., 2017

ZDB-PUB-170318-5
PMID:28302747