Distinct roles forXenopusTcf/Lef genes in mediating specific responses to Wnt/β-catenin signalling in mesoderm development

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Abstract
Tcf/Lef transcription factors and β-catenin mediate canonical Wnt signalling, which plays remarkably diverse roles in embryonic development, stem cell renewal and cancer progression. To investigate the molecular mechanisms allowing for these diverse yet specific functions, we studied the several distinct roles for Wnt/β-catenin signalling in early Xenopus development: establishing the dorsal body axis; regulating mesoderm induction; and subsequent ventrolateral patterning. Our previous experiments and the expression patterns of Tcf/Lef factors during these embryonic stages led us to examine whether different Tcf/Lef factors mediate these distinct events downstream of canonical Wnt/β-catenin signalling. By manipulating gene expression with morpholino-driven gene knockdown and capped RNA-mediated rescue, we show that genes encoding different Tcf/Lef transcription factors mediate distinct responses to Wnt signalling in early Xenopus development: Tcf1 and Tcf3 genes are non-redundantly required in mesoderm induction for mediating primarily transcriptional activation and repression, respectively; while ventrolateral patterning requires both Tcf1 and Lef1 genes to express sufficient levels of transcription-activating Tcf factors. Our investigation further identifies that motifs within their central domain, rather than their C-terminus, determine the particular molecular function of Tcf/Lef factors. These findings suggest that Tcf/Lef genes encode factors of different activities, which function together in antagonistic or synergistic ways to modulate the intensity and outcome of Wnt/β-catenin signalling and to trigger tissue-specific responses.