Editors' ChoiceDevelopment

The Repressor Within

Science Signaling  13 Sep 2011:
Vol. 4, Issue 190, pp. ec253
DOI: 10.1126/scisignal.4190ec253

Precise regulation of signaling through the Wnt pathway is required in various contexts for regulating cell fate, differentiation, and homeostasis. Various mechanisms exist to prevent Wnts from activating their receptors, and now Vacik et al. have identified an additional mechanism that antagonizes Wnt signaling at the level of transcriptional targets. In the vertebrate central nervous system (CNS), sonic hedgehog (Shh) antagonizes Wnt signaling to determine cell fates along the dorsoventral (DV) axis. Shh signaling in ventral cells induces production of the ventral anterior homeobox 1 and 2 (Vax1 and Vax 2) transcription factors. Vacik et al. identified a Vax2 binding site in an intron of Tcf7l2, which encodes a transcriptional coactivator that mediates Wnt signaling. Expression of Tcf7l2 from this internal promoter produced several truncated transcripts, all of which encoded a truncated version of Tcf7l2 that acted as a dominant-negative transcriptional repressor (dnTcf7l2). Vax2 was present in the ventral retina of the mouse embryo, where Shh signaling promotes ventral cell fates, and dnTcf7l2 was expressed throughout the retina. Expression of dnTcf7l was specifically lost in ventral retinal cells in Vax2–/– mutants, whereas the expression of full-length Tcf7l2 was unaffected. Expression of several genes that encode other Wnt signaling repressors was also reduced in the ventral retina of Vax2–/– mutants, and sequence analysis identified putative Vax2 binding sites in the introns of these genes. dnTcf7l2 transcripts were also expressed in the heads of frog embryos, and knocking down dnTcf7l2 resulted in phenotypes similar to those of mice lacking the Wnt signaling inhibitor Dickkopf1. The Tcf7l2 internal promoter was very highly conserved between human and chick (99.2%) and human and puffer fish (85.8%), indicating that this mode of regulating Tcf7l2 activity—and thus Wnt signaling—is important in vivo and that additional factors may regulate expression of dnTcf7l2 in tissues lacking Vax2 (see the Perspective by Grove).

T. Vacik, J. L. Stubbs, G. Lemke, A novel mechanism for the transcriptional regulation of Wnt signaling in development. Genes Dev. 25, 1783–1795 (2011). [Abstract] [Full Text]

E. A. Grove, Wnt signaling meets internal dissent. Genes Dev. 25, 1759–1762 (2011). [Abstract] [Full Text]