A Wnt1-regulated genetic network controls the identity and fate of midbrain-dopaminergic progenitors in vivo.
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.
Prakash
Nilima
N
GSF-National Research Center for Environment and Health, Technical University Munich, Institute of Developmental Genetics, Ingolstaedter Landstrasse 1, 85764 Munich/Neuherberg, Germany.
Brodski
Claude
C
Naserke
Thorsten
T
Puelles
Eduardo
E
Gogoi
Robindra
R
Hall
Anita
A
Panhuysen
Markus
M
Echevarria
Diego
D
Sussel
Lori
L
Weisenhorn
Daniela M Vogt
DM
Martinez
Salvador
S
Arenas
Ernest
E
Simeone
Antonio
A
Wurst
Wolfgang
W
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D000090322:Homeobox Protein Nkx-2.2; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008636:Mesencephalon / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008863:Microspheres; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology*; D051155:Wnt1 Protein / Q000378:metabolism*
D000090322:Homeobox Protein Nkx-2.2; C000715627:Nkx2-2 protein, mouse; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse