Developmentally regulated <i>Tcf7l2</i> splice variants mediate transcriptional repressor functions during eye formation.

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 <i>tcf7l2</i>alternative splice variants and show that only variants that include exon five or an analogous human <i>tcf7l2</i> variant can effectively provide compensatory repressor function to restore eye formation in embryos lacking <i>tcf7l1a/tcf7l1b</i> function. Knockdown of exon five specific <i>tcf7l2</i> variants in <i>tcf7l1a</i> 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 <i>tcf7l2</i> can influence the transcriptional output of the Wnt pathway.