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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 tcf7l2 alternative 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., Competing Interests: RY, KE, VF, MA, JG, TD, SW No competing interests declared, (© 2019, Young et al.)

Mediator-associated kinases CDK8/19 are context-dependent drivers or suppressors of tumorigenesis. Their inhibition is predicted to have pleiotropic effects, but it is unclear whether this will impact on the clinical utility of CDK8/19 inhibitors. We discovered two series of potent chemical probes with high selectivity for CDK8/19. Despite pharmacodynamic evidence for robust on-target activity, the compounds exhibited modest, though significant, efficacy against human tumor lines and patient-derived xenografts. Altered gene expression was consistent with CDK8/19 inhibition, including profiles associated with super-enhancers, immune and inflammatory responses and stem cell function. In a mouse model expressing oncogenic beta-catenin, treatment shifted cells within hyperplastic intestinal crypts from a stem cell to a transit amplifying phenotype. In two species, neither probe was tolerated at therapeutically-relevant exposures. The complex nature of the toxicity observed with two structurally-differentiated chemical series is consistent with on-target effects posing significant challenges to the clinical development of CDK8/19 inhibitors., Competing Interests: PAC: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. M-JO-R: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. RT: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. OA-P: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. GB: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. WC: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. SC: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. SEB: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. CE: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. SG: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. ADHB: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. PH: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. SMH: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. WK: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. AM: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. FRa: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. TR: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. FRo: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. KS: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. SS: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. RS: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. MV: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. SW: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. JB: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. AB: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. SAE: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. SH: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. KU: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. PW: Current or former employee of The Institute of Cancer Research, which has a commercial interest in the development of WNT pathway inhibitors. DW: Current or former employee of Merck KGaA (Darmstadt, Germany), which has a commercial interest in the development of WNT pathway inhibitors. The other authors declare that no competing interests exist.