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The Journal of Neuroscience, September 5, 2007, 27(36):9757-9768; doi:10.1523/JNEUROSCI.0763-07.2007

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Development/Plasticity/Repair
Activation of the Wnt–ßCatenin Pathway in a Cell Population on the Surface of the Forebrain Is Essential for the Establishment of Olfactory Axon Connections

Ambra A. Zaghetto,¹ Sara Paina,¹ Stefano Mantero,¹ Natalia Platonova,¹ Paolo Peretto,² Serena Bovetti,^2,3 Adam Puche,³ Stefano Piccolo,⁴ and Giorgio R. Merlo¹

¹Dulbecco Telethon Institute-Consiglio Nazionale delle Ricerche Institute for Biomedical Technologies Milano, 20090 Segrate, Italy, ²Department of Animal and Human Biology, University of Torino, 10123 Torino, Italy, ³Department of Anatomy and Neurobiology, School of Medicine, University of Maryland, Baltimore, Maryland 21201, and ⁴Department of Histology, Microbiology, and Medical Biotechnologies, School of Medicine, University of Padova, 35122 Padova, Italy

Correspondence should be addressed to Dr. Giorgio R. Merlo, Dulbecco Telethon Institute-Consiglio Nazionale delle Ricerche Institute for Biomedical Technologies, Via F.lli Cervi 93, 20090 Segrate (Milan), Italy. Email: gmerlo{at}dti.telethon.it

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. Using Wnt–ßcatenin reporter mice, we identify a novel Wnt-responsive resident cell population, located in a Frizzled7 expression domain at the surface of the embryonic FB, along the trajectory of incoming ORN axons. Organotypic slice cultures that recapitulate olfactory-associated Wnt–ßcatenin activation show that the ßcatenin response depends on a placode-derived signal(s). Likewise, in Dlx5–/– embryos, in which the primary connections fail to form, Wnt–ßcatenin response on the surface of the FB is strongly reduced. The olfactory placode expresses a number of ßcatenin-activating Wnt genes, and the Frizzled7 receptor transduces the "canonical" Wnt signal; using Wnt expression plasmids we show that Wnt5a and Wnt7b are sufficient to rescue ßcatenin 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.

Key words: Wnt; Frizzled; ßcatenin; olfactory; axon; connectivity

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Received Oct. 10, 2006; revised June 29, 2007; accepted July 4, 2007.

Correspondence should be addressed to Dr. Giorgio R. Merlo, Dulbecco Telethon Institute-Consiglio Nazionale delle Ricerche Institute for Biomedical Technologies, Via F.lli Cervi 93, 20090 Segrate (Milan), Italy. Email: gmerlo{at}dti.telethon.it

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