Wnt/beta-Catenin Signaling Blockade Promotes Neuronal Induction and Dopaminergic Differentiation in Embryonic Stem Cells

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Year of publication 2009
Type Article in Periodical
Magazine / Source Stem Cells
MU Faculty or unit

Faculty of Science

Field Genetics and molecular biology
Keywords embryonic stem cells ; Wnt pathway ; dopaminergic neurons ; Wnt/ -catenin signaling
Description Embryonic stem cells (ESCs) represent not only a promising source of cells for cell replacement therapy, but also a tool to study the molecular mechanisms underlying cellular signaling and dopaminergic (DA) neuron development. One of the main regulators of DA neuron development is Wnt signaling. Here we used mouse ESCs (mESCs) lacking Wnt1 or the low-density-lipoprotein receptor-related protein 6 (LRP6) to decipher the action of Wnt/ -catenin signaling on DA neuron development in mESCs. We provide evidence that the absence of LRP6 abrogates responsiveness of mESCs to Wnt ligand stimulation. Using two differentiation protocols we show that the loss of Wnt1 or LRP6 increases neuroectodermal differentiation and the number of mESC-derived DA neurons. These effects were similar to those observed following treatment of mESCs with the Wnt/ -catenin pathway inhibitor, Dickkopf1 (Dkk1). Combined, our results show that decreases in Wnt/ -catenin signaling enhance neuronal and DA differentiation of mESCs. These findings suggest: i) that Wnt1 or LRP6 are not strictly required for the DA differentiation of mESCs in vitro, ii) that the levels of morphogens and their activity in ESC cultures need to be optimized in order to improve DA differentiation, and iii) that by enhancing the differentiation and number of ESC-derived DA neurons with Dkk1, the application of ESCs for cell replacement therapy in Parkinson's disease may be improved.
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