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First published online 23 January 2007
doi: 10.1242/jcs.03368

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Wnt-5a induces Dishevelled phosphorylation and dopaminergic differentiation via a CK1-dependent mechanism

Vítzslav Bryja^{* ¶,}, Gunnar Schulte^{* ¶,}, Nina Rawal^{* ¶}, Alexandra Grahn^{* ¶} and Ernest Arenas

Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden

Author for correspondence (e-mail: ernest.arenas{at}ki.se)

Accepted 1 December 2006

Previously, we have shown that Wnt-5a strongly regulates dopaminergic neuron differentiation by inducing phosphorylation of Dishevelled (Dvl). Here, we identify additional components of the Wnt-5a-Dvl pathway in dopaminergic cells. Using in vitro gain-of-function and loss-of-function approaches, we reveal that casein kinase 1 (CK1) and CK1 are crucial for Dvl phosphorylation by non-canonical Wnts. We show that in response to Wnt-5a, CK1 binds Dvl and is subsequently phosphorylated. Moreover, in response to Wnt-5a or CK1, the distribution of Dvl changed from punctate to an even appearance within the cytoplasm. The opposite effect was induced by a CK1 kinase-dead mutant or by CK1 inhibitors. As expected, Wnt-5a blocked the Wnt-3a-induced activation of -catenin. However, both Wnt-3a and Wnt-5a activated Dvl2 by a CK1-dependent mechanism in a cooperative manner. Finally, we show that CK1 kinase activity is necessary for Wnt-5a-induced differentiation of primary dopaminergic precursors. Thus, our data identify CK1 as a component of Wnt-5a-induced signalling machinery that regulates dopaminergic differentiation, and suggest that CK1/-mediated phosphorylation of Dvl is a common step in both canonical and non-canonical Wnt signalling.

Key words: Casein kinase 1/, Dishevelled, Wnt-5a, Dopaminergic neurons, Non-canonical Wnt signalling, siRNA

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