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Molecular and Cellular Biology, April 2008, p. 2368-2379, Vol. 28, No. 7
0270-7306/08/$08.00+0     doi:10.1128/MCB.01780-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Wnt-3a and Dickkopf-1 Stimulate Neurite Outgrowth in Ewing Tumor Cells via a Frizzled3- and c-Jun N-Terminal Kinase-Dependent Mechanism{triangledown}

Yoshimi Endo,1 Elspeth Beauchamp,2 David Woods,1 William G. Taylor,1 Jeffrey A. Toretsky,2 Aykut Üren,2 and Jeffrey S. Rubin1*

Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892,1 Georgetown University Medical Center, Lombardi Cancer Center, Washington, DC 200572

Received 27 September 2007/ Returned for modification 23 October 2007/ Accepted 9 January 2008

Recombinant Wnt-3a stimulated the rapid formation of elongated processes in Ewing sarcoma family tumor (ESFT) cells that were identified as neurites. The processes stained positively for polymerized actin and microtubules as well as synapsin I and growth-associated protein 43. Inhibition of the Wnt receptor, Frizzled3 (Fzd3), with antiserum or by short interfering RNA (siRNA) markedly reduced neurite extension. Knockdown of Dishevelled-2 (Dvl-2) and Dvl-3 also suppressed neurite outgrowth. Surprisingly, disruption of the Wnt/Fzd/lipoprotein receptor-related protein (LRP) complex and the associated β-catenin signaling by treating cells either with the Wnt antagonist Dickkopf-1 (Dkk1) or LRP5/LRP6 siRNA enhanced neuritogenesis. Neurite outgrowth induced by Dkk1 or with LRP5/LRP6 siRNA was inhibited by secreted Fzd-related protein 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 β-catenin pathway to Fzd3-mediated, noncanonical signaling that is responsible for neurite formation. In particular, c-Jun amino-terminal kinase (JNK) was important for neurite outgrowth stimulated by both 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.

* Corresponding author. Mailing address: National Cancer Institute, Bldg. 37, Room 2042, 37 Convent Drive, MSC 4256, Bethesda, MD 20892-4256. Phone: (301) 496-4265. Fax: (301) 496-8479. E-mail: rubinj{at}mail.nih.gov

{triangledown} Published ahead of print on 22 January 2008.

Molecular and Cellular Biology, April 2008, p. 2368-2379, Vol. 28, No. 7
0270-7306/08/$08.00+0     doi:10.1128/MCB.01780-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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