Embryonic Stem Cells/Induced Pluripotent Stem Cells

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Wnt/β-Catenin Signaling Blockade Promotes Neuronal Induction and Dopaminergic Differentiation in Embryonic Stem Cells†‡§

  1. Lukás̆ C̆ajánek1,
  2. Diogo Ribeiro1,
  3. Isabel Liste1,2,
  4. Clare L. Parish1,3,
  5. Vítĕzslav Bryja1,4,¶,*,
  6. Ernest Arenas1,‖,*

Article first published online: 1 SEP 2009

DOI: 10.1002/stem.210

Issue

STEM CELLS

STEM CELLS

Volume 27, Issue 12, pages 2917–2927, December 2009

Additional Information

How to Cite

C̆ajánek, L., Ribeiro, D., Liste, I., Parish, C. L., Bryja, V. and Arenas, E. (2009), Wnt/β-Catenin Signaling Blockade Promotes Neuronal Induction and Dopaminergic Differentiation in Embryonic Stem Cells. STEM CELLS, 27: 2917–2927. doi: 10.1002/stem.210

Author Information

  1. 1

    Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden

  2. 2

    Center of Molecular Biology “Severo Ochoa” (CSIC-UAM), Autonomous University of Madrid, Madrid, Spain

  3. 3

    Howard Florey Institute, University of Melbourne, Parkville, Victoria, Australia

  4. 4

    Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic, and Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic

  1. Telephone: +420-532146226; Fax: +420-541211214

  2. ‖

    Telephone: +46-8-52487663; Fax: +46-8-34 1960

*Institute of Experimental Biology, Faculty of Science, Masaryk University, CZ-611 37 Brno, Czech Republic

  1. †

    Author contributions: LC: conception and design, collection and/or assembly of data, data analyses and interpretation, manuscript writing, final approval of manuscript; DR: collection and/or assembly of data, data analyses and interpretation; IL: collection and/or assembly of data, data analyses and interpretation; CLP: collection and/or assembly of data, data analyses and interpretation; VB: conception and design, data analyses and interpretation, manuscript writing; EA: conception and design, fund raising, data analyses and interpretation, manuscript writing, final approval of manuscript.

  2. ‡

    First published online in STEM CELLS EXPRESS September 1, 2009.

  3. §

    Disclosure of potential conflicts of interest is found at the end of this article.

Publication History

  1. Issue published online: 14 DEC 2009
  2. Article first published online: 1 SEP 2009
  3. Accepted manuscript online: 1 SEP 2009 12:00AM EST
  4. Manuscript Accepted: 19 AUG 2009
  5. Manuscript Received: 19 MAR 2009

Funded by

  • European Union (Neurostemcell)
  • Swedish Foundation for Strategic Research
  • Swedish Research Council
  • Norwegian Research Council and Karolinska Institute
  • Ministry of Education, Youth, and Sports of the Czech Republic. Grant Number: MSM0021622430
  • Academy of Sciences of the Czech Republic. Grant Numbers: AVOZ50040507, AVOZ50040702
  • EMBO Installation Grant and Czech Science Foundation. Grant Number: 204/09/0498
  • Karolinska Institute. Grant Number: 6110/06-225
  • Foundation for Science and Technology from the Portuguese Government. Grant Number: SFRH/BD/24585/2005
  • Human Frontiers Science Program long-term fellowship
  • National Health and Medical Research Council, Australia, CJ Martin fellowship

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Keywords:

  • Embryonic stem cells;
  • Wnt pathway;
  • Dopaminergic neurons;
  • Wnt/β-catenin signaling

Abstract

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/β-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/β-catenin pathway inhibitor Dickkopf1 (Dkk1). Combined, our results show that decreases in Wnt/β-catenin signaling enhance neuronal and DA differentiation of mESCs. These findings suggest that: 1) Wnt1 or LRP6 are not strictly required for the DA differentiation of mESCs in vitro, 2) the levels of morphogens and their activity in ESC cultures need to be optimized to improve DA differentiation, and 3) 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. STEM CELLS 2009;27:2917–2927

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