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First published online 2 November 2004
doi: 10.1242/jcs.01505

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GSK-3ß inhibition/ß-catenin stabilization in ventral midbrain precursors increases differentiation into dopamine neurons

Gonçalo Castelo-Branco^*, Nina Rawal^* and Ernest Arenas

Laboratory of Molecular Neurobiology, Medical Biochemistry and Biophysics, Karolinska Institute, Scheeles väg 1, A1, plan 2, 17177 Stockholm, Sweden

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

Accepted 20 August 2004

Wnts are important regulators of dopamine (DA) neuron differentiation in the developing ventral mesencephalon and could thus serve as potential tools in the treatment of Parkinson's disease. In this study, we investigate whether established intracellular Wnt signalling components could modulate the development of DA neurons. Two chemical inhibitors of glycogen synthase kinase (GSK)-3ß, indirubin-3-monoxime and kenpaullone, were found to increase neuronal differentiation in ventral mesencephalon precursor cultures. In addition, the GSK-3ß-specific inhibitor kenpaullone increased the size of the DA neuron population through conversion of precursors expressing the orphan nuclear receptor-related factor 1 into tyrosine hydroxylase positive neurons, thereby mimicking an effect of Wnts. We show that GSK-3ß inhibitors stabilized ß-catenin and that overexpression of ß-catenin in ventral mesencephalic precursors resulted in increased DA differentiation. The three- to fivefold increase in DA differentiation of precursor cells by GSK-3ß inhibitors suggests that such compounds could be used to improve stem/precursor cell therapy approaches in Parkinson's disease.

Key words: GSK-3ß, ß-catenin, Dopamine, Neuron, Wnt

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