Developmentally regulatedtcf7l2splice 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 signalling elicits such a diversity of biological outcomes are poorly understood. Here, we study alternatively spliced tcf7l2 in zebrafish and show that only splice variants that include exon 5 and an analogous human tcf7l2 variant can effectively provide compensatory repressor function to restore eye formation in embryos lacking tcf7l1a/tcf7l1b function. Knockdown of exon 5 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.