Inhibitory Gli3 activity negatively regulates Wnt/β-catenin signaling

The Hedgehog (Hh) and Wingless (Writ) families of secreted signaling molecules have key roles in embryonic development and adult tissue homeostasis [1-3]. In the developing neural tube, Writ and Shh, emanating from dorsal and ventral regions, respectively, have been proposed to govern the proliferation and survival of neural progenitors [4-10]. Surprisingly, Shh is required for the growth and survival of cells in both ventral and dorsal neural tube [11]. Here we demonstrate that inhibition of Shh signaling causes a reduction in Wnt-mediated transcriptional activation. This reduction requires GO. Assays in embryos and cell lines indicate that repressor forms of the Hh-regulated transcription factor, GIi3 (GIi3R), which are generated in the absence of Hh signaling, inhibit canonical Writ signaling. GIi3R acts by antagonizing active forms of the Writ transcriptional effector, beta-catenin. Consistent with this, GIi3R appears to physically interact with the carboxy-terminal domain of beta-catenin, a region that includes the transactivation domain. These data off er an explanation for the proliferative defects in Shh null embryos and suggest a novel mechanism for crosstalk between the Hh and Wnt pathways.