GSK-3beta inhibition/beta-catenin stabilization in ventral midbrain precursors increases differentiation into dopamine neurons.
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)-3beta, indirubin-3-monoxime and kenpaullone, were found to increase neuronal differentiation in ventral mesencephalon precursor cultures. In addition, the GSK-3beta-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-3beta inhibitors stabilized beta-catenin and that overexpression of beta-catenin in ventral mesencephalic precursors resulted in increased DA differentiation. The three- to fivefold increase in DA differentiation of precursor cells by GSK-3beta inhibitors suggests that such compounds could be used to improve stem/precursor cell therapy approaches in Parkinson's disease.
Castelo-Branco
Gonçalo
G
Laboratory of Molecular Neurobiology, Medical Biochemistry and Biophysics, Karolinska Institute, Scheeles väg 1, A1, plan 2, 17177 Stockholm, Sweden.
Rawal
Nina
N
Arenas
Ernest
E
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001921:Brain / Q000196:embryology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000737:chemistry* / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D007381:Intermediate Filament Proteins / Q000737:chemistry; D008636:Mesencephalon / Q000196:embryology*; D009419:Nerve Tissue Proteins / Q000737:chemistry; D064231:Nestin; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010091:Oximes / Q000494:pharmacology; D010300:Parkinson Disease / Q000628:therapy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D013997:Time Factors; D015534:Trans-Activators / Q000737:chemistry* / Q000378:metabolism; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation; D014746:Vimentin / Q000737:chemistry; D051176:beta Catenin
D001552:Benzazepines; C495270:CTNNB1 protein, human; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; D007211:Indoles; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577486:Nes protein, rat; D064231:Nestin; D010091:Oximes; D012333:RNA, Messenger; D015534:Trans-Activators; D014746:Vimentin; D051176:beta Catenin; C474021:indirubin-3'-monoxime; C119620:kenpaullone; D014446:Tyrosine 3-Monooxygenase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D004298:Dopamine