The balance of TCF7L2 variants with differential activities in Wnt-signaling is regulated by lithium in a GSK3β-independent manner

► Identification of a novel effect of lithium on the expression of TCF7L2 RNA isoforms and protein variants. ► The extent of lithium-induced TCF7L2 form switch mirrors cell responsiveness to Wnt/β-catenin signaling. ► Demonstration that lithium has dual GSK3β-dependent and -independent effects on TCF7L2 expression. ► Demonstration that TCF7L2 expression is repressed by the transcriptionally active TCF7L2E form. ► Evidence for a lithium-induced de-repression mechanism of TCF7L2 expression via TCF7L2 variant switch.