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 tcf7l2alternative 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.
Keywords: alternative splicing; developmental biology; eye development; tcf7l2; zebrafish.
© 2019, Young et al.
Conflict of interest statement
RY, KE, VF, MA, JG, TD, SW No competing interests declared
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A Context-Specific Cardiac β-Catenin and GATA4 Interaction Influences TCF7L2 Occupancy and Remodels Chromatin Driving Disease Progression in the Adult HeartLM Iyer et al. Nucleic Acids Res 46 (6), 2850-2867. PMID 29394407.Chromatin remodelling precedes transcriptional and structural changes in heart failure. A body of work suggests roles for the developmental Wnt signalling pathway in card …
Molecular Function of TCF7L2: Consequences of TCF7L2 Splicing for Molecular Function and Risk for Type 2 DiabetesO Hansson et al. Curr Diab Rep 10 (6), 444-51. PMID 20878273. - ReviewTCF7L2 harbors the variant with the strongest effect on type 2 diabetes (T2D) identified to date, yet the molecular mechanism as to how variation in the gene increases th …
Current Understanding and Dispute on the Function of the Wnt Signaling Pathway Effector TCF7L2 in Hepatic GluconeogenesisT Jin. Genes Dis 3 (1), 48-55. PMID 30258876. - ReviewApproximately 10 years ago, the Wnt signaling pathway effector TCF7L2 (=TCF-4) was recognized as a type 2 diabetes (T2D) risk gene through a genome wide association study …
- Bailey KA, Savic D, Zielinski M, Park SY, Wang LJ, Witkowski P, Brady M, Hara M, Bell GI, Nobrega MA. Evidence of non-pancreatic beta cell-dependent roles of Tcf7l2 in the regulation of glucose metabolism in mice. Human Molecular Genetics. 2015;24:1646–1654. doi: 10.1093/hmg/ddu577. - DOI - PMC - PubMed
- International Joint Project/Royal Society/International
- MR/L003775/1/MRC_/Medical Research Council/United Kingdom
- Marie Curie Incoming International Fellowship/H2020 Marie Skłodowska-Curie Actions/International