Eukaryotic initiation factor 4A3 inhibits Wnt/β-catenin signaling and regulates axis formation in zebrafish embryos
Bo Wang1, Xiaozhi Rong1,2, Yumei Zhou1
1Key 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.
Abstract:
A key step in the activation of canonical Wnt signaling is the interaction between β-catenin and Tcf/Lefs that forms the transcription activation complex and facilitates the expression of target genes. Eukaryotic initiation factor 4A3 (EIF4A3) is an ATP-dependent DEAD box-family RNA helicase and acts as a core subunit of the exon junction complex (EJC) to control a series of RNA post-transcriptional processes. In this study, we uncover that EIF4A3 functions as a Wnt inhibitor by interfering with the formation of β-catenin/Tcf transcription activation complex. As Wnt stimulation increases, accumulated β-catenin displaces EIF4A3 from a transcriptional complex with Tcf/Lef, allowing the active complex to facilitate the expression of target genes. In zebrafish embryos, eif4a3 depletion inhibited the development of the dorsal organizer and pattern formation of the anterior neuroectoderm by increasing Wnt/β-catenin signaling. Conversely, overexpression of eif4a3 decreased Wnt/β-catenin signaling and inhibited the formation of the dorsal organizer before gastrulation. Our results reveal previously unreported roles of EIF4A3 in the inhibition of Wnt signaling and the regulation of embryonic development in zebrafish.
Insights
Eukaryotic initiation factor 4A3 (EIF4A3) inhibits Wnt signaling by blocking β-catenin/Tcf complex formation. Its depletion in zebrafish disrupts embryonic development, revealing a novel role in Wnt pathway regulation.
Area of Science:
- Molecular Biology
- Developmental Biology
- Cell Signaling
Background:
- Canonical Wnt signaling is crucial for embryonic development, involving β-catenin and Tcf/Lef transcription factors.
- Eukaryotic initiation factor 4A3 (EIF4A3) is an RNA helicase and core subunit of the exon junction complex (EJC), regulating RNA post-transcriptional processes.
Purpose of the Study:
- To investigate the role of EIF4A3 in Wnt signaling and embryonic development.
- To determine how EIF4A3 interacts with the β-catenin/Tcf transcription complex.
Main Methods:
- Studied the interaction between EIF4A3 and the β-catenin/Tcf complex in vitro and in cell models.
- Utilized zebrafish (Danio rerio) embryos to examine the effects of eif4a3 depletion and overexpression on Wnt signaling and development.
Main Results:
- EIF4A3 inhibits Wnt signaling by preventing the formation of the β-catenin/Tcf transcription activation complex.
- Wnt stimulation leads to β-catenin displacing EIF4A3, enabling target gene expression.
- Depletion of eif4a3 in zebrafish embryos resulted in increased Wnt/β-catenin signaling, affecting dorsal organizer and anterior neuroectoderm development.
- Overexpression of eif4a3 suppressed Wnt/β-catenin signaling and inhibited dorsal organizer formation.
Conclusions:
- EIF4A3 acts as a novel inhibitor of the canonical Wnt signaling pathway.
- EIF4A3 plays a critical role in regulating zebrafish embryonic development through modulation of Wnt signaling.
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