Our objective was to determine how Wnt signaling regulates the patterning of regions that will give rise to neurons (neuroectoderm) versus those that do not. The anterior neuroectoderm domain forms where Wnt is antagonized whereas epidermal ectoderm differentiates where Wnt is active. At least three different Wnt pathways, Wnt/beta-catenin, Wnt/PCP and Wnt/Ca+2, are involved in separating the domains of these two types of ectoderm and at least three different regulators of Wnt signaling, Dkk1, sFRP1/5 and Dkk3, are ultimately expressed in the anterior neuroectoderm where Wnt signaling is low. We elucidated an intricate, interconnected set of interactions among the Wnt signaling branches that eliminate the ubiquitous, maternally driven anterior neuroectoderm regulatory state from all but the anterior-most cells of the embryo. First, early maternally derived signaling through Wnt/beta-catenin removes it from posterior blastomeres and activates production of at least two Wnt ligands, Wnt1 and Wnt8, that signal through the Wnt/JNK pathway via the Wnt receptor, Frizzled 5/8, to eliminate anterior neuroectoderm fate from most anterior blastomeres, except those immediately around the anterior pole. Both Wnt/beta-catenin and Wnt/JNK pathways are slowed by signaling through another Wnt receptor, Frizzled 1/2/7;this serves a coordinating function to properly regulate fates of individual blastomeres as they separate during cleavage and interact via both anterior-posterior and dorsal-ventral (nodal-BMP) patterning mechanisms. Fz5/8-dependent elimination of the anterior neural regulatory state is blocked by production of the Wnt antagonist, Dkk1 in the anterior neurectoderm. Interestingly, Dkk1 expression depends on Fz5/8 but then negatively feeds back to inhibit its expression. In all but the anterior-most cells Fz5/8 activity is maintained, in part by a positive feedback on its own transcription. How Fz5/8 transcription is maintained in anterior cells in the presence of Dkk1 is not yet understood, but may depend on Dkk3, which is expressed specifically in anterior cells and is an apparent potentiator of Wnt signaling. These studies have uncovered a set of unexpected and surprisingly complex interactions among different Wnt pathways in early patterning as well as unexpected roles for Wnt/PCP and Wnt/Ca+2 in regulating early ectodermal cell fate decisions. This network of Wnt signaling is likely conserved among deuterostome embryos, based on reported gene expression patterns in hemichordates and cephalochordates and isolated loss-of-function studies in zebrafish embryos.
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