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A novel mechanism for the transcriptional regulation of Wnt signaling in development

08/18/2011

A novel mechanism for the transcriptional regulation of Wnt signaling in development

Tomas Vacik, Jennifer L Stubbs, and Greg Lemke

Two mutually antagonistic sets of morphogens – Sonic hedgehog (Shh) and Wnt proteins – establish dorsal/ventral polarity in the embryonic eye and forebrain. The Lemke lab previously identified the Vax1 and Vax2 transcription factors as key effectors of the ventralizing Shh signal: Vax1/2 activate a network of ventral genes and simultaneously block genes involved in dorsal development. In this paper, Vacik et al. now reveal the underlying mechanism. Using a combination of genetic, biochemical and cell biological techniques, Vacik et al. found that Vax2 binds to a promoter located in intron 5 of the Tcf7l2, which drives expression of a truncated isoform that lacks the amino-terminus domain that is required for binding to the Wnt effector, beta-catenin. Thus, this dominant-negative isoform, dnTcf7l2, effectively blocks all canonical Wnt signaling. As evidence of this, the authors show that specific deletion of dnTcf7l2 during frog development results in headless embryos that lack a forebrain entirely. The fundamental role of this regulatory mechanism is underscored by the author's point that "this internal promoter is very nearly the most highly conserved sequence of non-coding DNA across vertebrate genomes."

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