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JCS ePress
online publication date 2 Nov 2004
doi: 10.1242/jcs.01505
Research Article
GSK-3
inhibition/-catenin stabilization in ventral midbrain precursors increases differentiation into dopamine neurons
Gonçalo Castelo-Branco,
Nina Rawal,
and
Ernest Arenas*
* Author for correspondence (e-mail: ernest.arenas{at}mbb.ki.se)
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)-3
, indirubin-3-monoxime and kenpaullone, were found to increase neuronal differentiation in ventral mesencephalon precursor cultures. In addition, the GSK-3-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-3 inhibitors stabilized -catenin and that overexpression of -catenin in ventral mesencephalic precursors resulted in increased DA differentiation. The three- to fivefold increase in DA differentiation of precursor cells by GSK-3 inhibitors suggests that such compounds could be used to improve stem/precursor cell therapy approaches in Parkinson's disease.
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