title: Glutathione peroxidase 4 inhibits Wnt/β-catenin signaling and regulates dorsal organizer formation in zebrafish embryos.
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 zebrafishgpx4bpromotes embryonic dorsal organizer formation, whereas overexpression ofgpx4binhibits the development of the dorsal organizer. Depletion of humanGPX4and zebrafishgpx4b(GPX4/gpx4b) increases, whileGPX4/gpx4boverexpression decreases, Wnt/β-catenin signalingin vivoandin vitroFunctional 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.
authors.affiliation: Key Laboratory of Marine Drugs (Ocean University of China), Chinese Ministry of Education, and School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.|Institute of Evolution and Marine Biodiversity and College of Marine Biology, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.|Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, China.|Laboratory for Marine Drugs and Biological Products, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, China.
authors.forename: Xiaozhi
authors.initials: X
authors.lastname: Rong
authors.affiliation: Key Laboratory of Marine Drugs (Ocean University of China), Chinese Ministry of Education, and School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.
authors.forename: Yumei
authors.identifier: 0000-0001-9647-6369
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Marine Drugs (Ocean University of China), Chinese Ministry of Education, and School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.
authors.forename: Yunzhang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Marine Drugs (Ocean University of China), Chinese Ministry of Education, and School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.
authors.forename: Beibei
authors.identifier: 0000-0002-2922-4628
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Marine Drugs (Ocean University of China), Chinese Ministry of Education, and School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: Key Laboratory of Marine Drugs (Ocean University of China), Chinese Ministry of Education, and School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.
authors.forename: Caixia
authors.initials: C
authors.lastname: Wang
authors.affiliation: Key Laboratory of Marine Drugs (Ocean University of China), Chinese Ministry of Education, and School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.
authors.forename: Xiaoxia
authors.identifier: 0000-0001-5481-880X
authors.initials: X
authors.lastname: Gong
authors.affiliation: Key Laboratory of Marine Drugs (Ocean University of China), Chinese Ministry of Education, and School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.
authors.forename: Peipei
authors.identifier: 0000-0002-1535-3971
authors.initials: P
authors.lastname: Tang
authors.affiliation: Key Laboratory of Marine Drugs (Ocean University of China), Chinese Ministry of Education, and School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Lu
authors.affiliation: Key Laboratory of Marine Drugs (Ocean University of China), Chinese Ministry of Education, and School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Evolution and Marine Biodiversity and College of Marine Biology, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.|Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, China.
authors.forename: Chengtian
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Marine Drugs (Ocean University of China), Chinese Ministry of Education, and School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China jfzhou@ouc.edu.cn.|Laboratory for Marine Drugs and Biological Products, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, China.
authors.forename: Jianfeng
authors.identifier: 0000-0001-5702-6664
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D064113:CRISPR-Cas Systems / Q000235:genetics; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000201:enzymology*; D019143:Evolution, Molecular; D018507:Gene Expression Regulation, Developmental; D005979:Glutathione Peroxidase / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D020897:Organizers, Embryonic / Q000201:enzymology*; D010641:Phenotype; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D012643:Selenium / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic; D060449:Wnt Signaling Pathway; D015027:Zebrafish / Q000196:embryology* / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015053:Zygote / Q000378:metabolism
chemical_list: D029961:Zebrafish Proteins; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; D012643:Selenium
keywords: Dorsal organizer; Glutathione peroxidase 4; Tcf/Lef; Wnt/β-catenin signaling; Zebrafish