Developmentally regulated tcf7l2 splice variants mediate transcriptional repressor functions during eye formation

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/Tcf signalling more generally elicits such a diversity of biological outcomes are poorly understood. Here, we identify an alternatively spliced tcf7l2 exon5 and show that only splice variants that include this exon provide compensatory repressor function to restore eye formation in zebrafish embryos lacking tcf7l1a/b function. Knockdown of tcf7l2 variants that include exon5 in tcf7l1a mutants also compromises eye formation and these variants can effectively compete with constitutively-active human VP16-TCF7L2 in reporter assays using Wnt target gene promoters. We show that the repressive activities of exon5 coded variants are likely explained by their higher affinity for Tle co-repressors. Furthermore, putatively phosphorylated residues in Tcf7l2 coded exon5 facilitate repressor activity. Our studies suggest that regulation of tcf7l2 splicing influences the level of transcriptional repression mediated by Wnt pathway.