Wnt/β-Catenin Signaling is Disrupted in the Extra-toes (Gli3Xt/Xt) Mutant from Early Stages of Forebrain Development, Concomitant with Anterior Neural Plate Patterning Defects

The zinc finger transcription factor Gli3 is essential for normal development of the forebrain. Mutant mice with no functional Gli3 (extra-toes, Gli3(Xt/Xt) mutants) display a massive reduction in the size of the telencephalic lobes and absence of dorsomedial telencephalic structures, including the cortical hem, which normally expresses a number of Wnt molecules essential for patterning the hippocampus. Dorsomedial telencephalic Wnt activity, transduced through the Wnt/beta-catenin signaling pathway, is also required for hippocampal specification and dorsoventral telencephalic patterning. Wnts whose normal expression is restricted to the cortical hem are completely absent in Gli3(Xt/Xt) embryos, but some expression of those Wnts with a broader expression domain persists, raising the possibility that Wnt/beta-catenin signaling may still be active in this mutant. We examined whether the Wnt expression that persists in the Gli3(Xt/Xt) mutant neocortex activates Wnt/beta-catenin signaling, using the BAT-gal transgenic reporter. We found Wnt/beta-catenin signaling consistently decreased in the forebrains of Gli3(Xt/Xt) mutants, even prior to the formation of the cortical hem. This is accompanied by a severe reduction in expression of Wnt7b and Wnt8b at the lateral edges of the anterior neural plate that will give rise to the pallium. In addition, we found a significant increase in the expression of rostroventral markers of the anterior neural plate that will give rise to the basal forebrain. Our data reveal that Gli3 is required at the neural plate stage to regulate Wnt expression and Wnt/beta-catenin signaling in the presumptive forebrain and confirm its previously proposed role in patterning the anterior neural plate. J. Comp. Neurol. 519:1640-1657, 2011. (c) 2011 Wiley-Liss, Inc.