Abstract
The atypical protein kinase C (aPKC) in complex with PAR3 and PAR6 is required for axon-dendrite differentiation, but the upstream factors responsible for regulating its activity are largely unknown. Here, we report that in cultured hippocampal neurons aPKC is directly regulated by Dishevelled (Dvl), an immediate downstream effector of Wnt. We found that downregulation of Dvl abrogated axon differentiation, whereas Dvl overexpression resulted in multiple axon formation. Interestingly, Dvl was associated with aPKC and this interaction resulted in aPKC stabilization and activation. Furthermore, the multiple axon formation resulting from Dvl overexpression was attenuated by expressing a dominant–negative aPKC in these neurons and overexpression of aPKC prevented the loss of axon caused by Dvl downregulation. Finally, Wnt5a, a noncanonical Wnt, activated aPKC and promoted axon differentiation. The Wnt5a effect on axon differentiation was attenuated by downregulating Dvl or inhibiting aPKC. Thus, Dvl–aPKC interaction can promote axon differentiation mediated by the PAR3–PAR6–aPKC complex.
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Acknowledgements
We are grateful to M. M. Poo and L. Mei for their critical reading of the manuscript, to X. He, C. Liu, I. Macara, H. Piwnica-Worms, Y. Rao, T. Saito, Y. Z. Wang, Z. Ke and J. Luo for reagents, and to Q. Hu for the assistance in imaging analysis. This work was supported in part by grants from National Natural Science Foundation of China (Nos. 90408026), Shanghai Science and Technology Development Foundation (03JC14078), “973” Program (2006CB806600), and Key State Research Program (2006CB943903) to Z.G.L.
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All authors contributed to experimental work and data analysis. Z.-G.L planned the project and wrote the manuscript.
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Zhang, X., Zhu, J., Yang, GY. et al. Dishevelled promotes axon differentiation by regulating atypical protein kinase C. Nat Cell Biol 9, 743–754 (2007). https://doi.org/10.1038/ncb1603
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DOI: https://doi.org/10.1038/ncb1603
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