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.
Highlights
Wnt signalling has a broad array of biological functions, from regional patterning and fate specification during embryonic development to tissue homeostasis and stem cell niche maintenance in adult organs (van Amerongen and Nusse, 2009; Nusse and Clevers, 2017)
Zebrafish tcf7l2 exon five is similar in size to human tcf7l2 exon 3a but instead, lies in a genomic location that in the human gene would be positioned between exons 4 and 5, where alternative human exon 4a is located (Figure 1D)
We show that there is extensive variety in splicing of zebrafish tcf7l2 throughout development and across adult tissues and that the exon five encoded region within Tcf7l2 influences its transcriptional repressor activity
Summary
Wnt signalling has a broad array of biological functions, from regional patterning and fate specification during embryonic development to tissue homeostasis and stem cell niche maintenance in adult organs (van Amerongen and Nusse, 2009; Nusse and Clevers, 2017). When cells are exposed to Wnt ligand, the destruction complex is disassembled and b-catenin is no longer phosphorylated and committed to degradation (MacDonald et al, 2009; Niehrs, 2012) This promotes the translocation of b-catenin to the nucleus where it displaces Gro/TLE co-repressors from interacting with Tcfs and activating the transcription of Wnt target genes
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