Activation of theWnt–βCatenin Pathway in a Cell Population on the Surface of the Forebrain Is Essential for the Establishment of Olfactory Axon Connections

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Abstract
A variety of signals governing early extension, guidance, and connectivity of olfactory receptor neuron (ORN) axons has been identified; however, little is known about axon–mesoderm and forebrain (FB)–mesoderm signals. UsingWnt–βcatenin reporter mice, we identify a novel Wnt-responsive resident cell population, located in aFrizzled7expression domain at the surface of the embryonic FB, along the trajectory of incoming ORN axons. Organotypic slice cultures that recapitulate olfactory-associated Wnt–βcatenin activation show that the βcatenin response depends on a placode-derived signal(s). Likewise, inDlx5−/− embryos, in which the primary connections fail to form,Wnt–βcatenin response on the surface of the FB is strongly reduced. The olfactory placode expresses a number of βcatenin-activating Wnt genes, and theFrizzled7receptor transduces the “canonical” Wnt signal; using Wnt expression plasmids we show that Wnt5a and Wnt7b are sufficient to rescue βcatenin activation in the absence of incoming axons. Finally, blocking the canonical Wnt pathway with the exogenous application of the antagonists Dikkopf-1 or secreted-Frizzled-receptor protein-2 prevents ORN axon contact to the FB. These data reveal a novel function for Wnt signaling in the establishment of periphery–CNS olfactory connections and highlight a complex interplay between cells of different embryonic origin for ORN axon connectivity.