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First published online December 8, 2005
doi: 10.1242/10.1242/dev.02181
1 GSF-National Research Center for Environment and Health, Technical University
Munich, Institute of Developmental Genetics, Ingolstaedter Landstrasse 1,
85764 Munich/Neuherberg, Germany, and Max-Planck-Institute of Psychiatry,
Kraepelinstrasse 2, 80804 Munich, Germany.
2 Ben-Gurion University of the Negev, Faculty of Health Sciences, Zlotowski
Center for Neuroscience, Department of Morphology, Be'er Sheva 84105,
Israel.
3 MRC Centre for Developmental Neurobiology, 4th floor, New Hunt's House, King's
College London, Guy's Campus, London Bridge, London SE1 UL, UK.
4 Laboratory of Molecular Neurobiology, MBB, Karolinska Institute, 17177
Stockholm, Sweden.
5 Instituto de Neurociencias, Universidad Miguel Hernandez, San Juan, 03550
Alicante, Spain.
6 Barbara Davis Center, University of Colorado Health Science Center, 4200 E.
9th Avenue, Denver, CO 8020, USA.
7 CEINGE Biotecnologie Avanzate, Via Comunale Margherita 482, 80145 Naples,
Italy.
8 Institute of Genetics and Biophysics `ABT', Via Guglielmo Marconi 12, 80125
Naples, Italy.
Authors for correspondence (e-mail:
wurst{at}gsf.de
and
antonio.simeone{at}kcl.ac.uk)
Accepted 25 October 2005
Midbrain neurons synthesizing the neurotransmitter dopamine play a central role in the modulation of different brain functions and are associated with major neurological and psychiatric disorders. Despite the importance of these cells, the molecular mechanisms controlling their development are still poorly understood. The secreted glycoprotein Wnt1 is expressed in close vicinity to developing midbrain dopaminergic neurons. Here, we show that Wnt1 regulates the genetic network, including Otx2 and Nkx2-2, that is required for the establishment of the midbrain dopaminergic progenitor domain during embryonic development. In addition, Wnt1 is required for the terminal differentiation of midbrain dopaminergic neurons at later stages of embryogenesis. These results identify Wnt1 as a key molecule in the development of midbrain dopaminergic neurons in vivo. They also suggest the Wnt1-controlled signaling pathway as a promising target for new therapeutic strategies in the treatment of Parkinson's disease.
Key words: Dopaminergic neuron, Development, Midbrain, Progenitor domain, Cell fate specification, Wnt1, Otx2, Nkx2-2, Mouse
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