MCB Accepts, published online ahead of print on 22 January 2008

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Mol. Cell. Biol. doi:10.1128/MCB.01780-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Wnt-3a and Dickkopf-1 stimulate neurite outgrowth in Ewing tumor cells via a Frizzled3- and JNK-dependent mechanism

Yoshimi Endo, Elspeth Beauchamp, David Woods, William G. Taylor, Jeffrey A. Toretsky, Aykut Üren, and Jeffrey S. Rubin^*

Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; Georgetown University Medical Center, Lombardi Cancer Center, Washington, D.C. 20057

^* To whom correspondence should be addressed. Email: rubinj{at}mail.nih.gov.

Recombinant Wnt-3a stimulated the rapid formation of elongated processes in Ewing sarcoma family tumor (ESFT) cells that were identified as neurites. They stained positively for polymerized actin and microtubules, as well as synapsin I and GAP-43. Inhibition of the Wnt receptor, Frizzled3 (Fzd3), with antiserum or by siRNA markedly reduced neurite extension. Knockdown of Dishevelled (Dvl) -2 and -3 also suppressed neurite outgrowth. Surprisingly, disruption of the Wnt/Fzd/LRP complex and the associated -catenin signaling, either by treating cells with the Wnt antagonist Dickkopf-1 (Dkk1) or LRP5/6 siRNA enhanced neuritogenesis. Neurite outgrowth induced by Dkk1 or LRP5/6 siRNA was inhibited by secreted Frizzled-related protein-1 (sFRP-1), a Wnt antagonist that binds directly to Wnt. Moreover, Dkk1 stimulation of neurite outgrowth was blocked by Fzd3 siRNA. These results suggested that Dkk1 shifted endogenous Wnt activity from the -catenin pathway to Fzd3-mediated, non-canonical signaling that is responsible for neurite formation. In particular, c-Jun amino-terminal kinase (JNK) was important for neurite outgrowth stimulated both by Wnt-3a and Dkk1. Our data demonstrate that Fzd3, Dvl and JNK activity mediate Wnt-dependent neurite outgrowth, and that ESFT cell lines will be useful experimental models for the study of Wnt-dependent neurite extension.

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