Wnt signaling through Dishevelled, Rac and JNK regulates dendritic development

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Abstract

Dendritic arborization is required for proper neuronal connectivity. Rho GTPases have been implicated in the regulation of dendrite development. However, the signaling pathways that impinge on these molecular switches remain poorly understood. Here we show that Wnt7b, which is expressed in the mouse hippocampus, increases dendritic branching in cultured hippocampal neurons. This effect is mimicked by the expression of Dishevelled (Dvl) and is blocked by Sfrp1, a secreted Wnt antagonist. Consistent with these findings, hippocampal neurons from mice lacking Dvl1 show reduced dendritic arborization. Activation of the canonical Wnt-Gsk3β pathway does not affect dendritic development. In contrast, Wnt7b and Dvl activate Rac and JNK in hippocampal neurons. Dominant-negative Rac, dominant-negative JNK or inhibition of JNK blocks Dvl-mediated dendritic growth. These findings demonstrate a new function for the non-canonical Wnt pathway in dendrite development and identify Dvl as a regulator of Rho GTPases and JNK during dendritic morphogenesis.

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Figure 1: Wnt7b is expressed in the mouse hippocampus and increases dendritic development.
Figure 2: Dvl is associated with the neuronal cytoskeleton and increases dendritic arborization.
Figure 3: The PDZ domain is required for Dvl function.
Figure 4: Dvl1 deficiency decreases dendritic arborization.
Figure 5: Dvl regulates dendritic development independently of the canonical Wnt pathway.
Figure 6: Dvl does not require Rho to regulate dendritic development.
Figure 7: Rac is required for Dvl function.
Figure 8: JNK is activated by Wnt7b and Dvl and is required for dendritogensis.

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Acknowledgements

We thank I. Simeonidis for breeding and genotyping Dvl1 mutant mice, S. Hughes and members of our lab for suggestions and comments on the manuscript, and K. Nobes, H. Xe, R. Kypta, J. Nathans and R. Davis for constructs. This work was funded by a Wellcome Trust grant (to P.C.S.).

Author information

Correspondence to Patricia C Salinas.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Sfrp1 does not induce apoptosis. (a) Hippocampal neurons exposed to CM from EGFP-expressing cells or Sfrp1-expressing cells exhibit the same number of TUNEL-labelled apoptotic nuclei than controls. (b) Quantification of three independent experiments shows that the presence of Sfrp1 does not change the percentage of apoptotic neurons. (JPG 28 kb)

Supplementary Fig. 2

Dvl1 deficiency affects dendritic growth but no dendritic initiation. Hippocampal neurons from wildtype and Dvl1 mutant mice cultured for 3, 6 and 9 d in vitro were stained for MAP2 to analyse dendritic development. The graph shows that Dvl1 mutant cultured for 3 d in vitro have similar dendritic length to neurons from wildtype animals. At 6 d in vitro, however, Dvl1 mutant neurons have significantly shorter dendrites than wildtype neurons. At 9 d in vitro this difference in dendritic length is more pronounced. These results demonstrate that Dvl1 deficiency results in a pronounced delay in dendritic growth in older cultures. (GIF 8 kb)

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Rosso, S., Sussman, D., Wynshaw-Boris, A. et al. Wnt signaling through Dishevelled, Rac and JNK regulates dendritic development. Nat Neurosci 8, 34–42 (2005) doi:10.1038/nn1374

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