PUBLICATION
Developmentally regulated Tcf7l2 splice variants mediate transcriptional repressor functions during eye formation
- Authors
- Young, R.M., Ewan, K.B., Ferrer, V.P., Allende, M.L., Godovac-Zimmermann, J., Dale, T.C., Wilson, S.W.
- ID
- ZDB-PUB-191213-10
- Date
- 2019
- Source
- eLIFE 8: (Journal)
- Registered Authors
- Allende, Miguel L., Ferrer, Veronica, Young, Rodrigo
- Keywords
- alternative splicing, developmental biology, eye development, tcf7l2, zebrafish
- MeSH Terms
-
- Animals
- Eye/embryology*
- Gene Expression Regulation, Developmental*
- HEK293 Cells
- Humans
- Protein Isoforms/biosynthesis*
- Protein Isoforms/genetics
- RNA Splicing*
- Transcription Factor 7-Like 2 Protein/biosynthesis*
- Transcription Factor 7-Like 2 Protein/genetics
- Transcription Factor 7-Like 2 Protein/metabolism
- Transcription, Genetic*
- Wnt Signaling Pathway
- Zebrafish
- Zebrafish Proteins/biosynthesis*
- Zebrafish Proteins/genetics
- PubMed
- 31829936 Full text @ Elife
Citation
Young, R.M., Ewan, K.B., Ferrer, V.P., Allende, M.L., Godovac-Zimmermann, J., Dale, T.C., Wilson, S.W. (2019) Developmentally regulated Tcf7l2 splice variants mediate transcriptional repressor functions during eye formation. eLIFE. 8:.
Abstract
Tcf7l2 mediates Wnt/β-Catenin signalling during development and is implicated in cancer and type-2 diabetes. The mechanisms by which Tcf7l2 and Wnt/β-Catenin signalling elicit such a diversity of biological outcomes are poorly understood. Here, we study the function of zebrafish tcf7l2alternative splice variants and show that only variants that include exon five or an analogous human tcf7l2 variant can effectively provide compensatory repressor function to restore eye formation in embryos lacking tcf7l1a/tcf7l1b function. Knockdown of exon five specific tcf7l2 variants in tcf7l1a mutants also compromises eye formation, and these variants can effectively repress Wnt pathway activity in reporter assays using Wnt target gene promoters. We show that the repressive activities of exon5-coded variants are likely explained by their interaction with Tle co-repressors. Furthermore, phosphorylated residues in Tcf7l2 coded exon5 facilitate repressor activity. Our studies suggest that developmentally regulated splicing of tcf7l2 can influence the transcriptional output of the Wnt pathway.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping