title: Tiam1 regulates the Wnt/Dvl/Rac1 signaling pathway and the differentiation of midbrain dopaminergic neurons.
abstract: Understanding the mechanisms that drive the differentiation of dopaminergic (DA) neurons is crucial for successful development of novel therapies for Parkinson's disease, in which DA neurons progressively degenerate. However, the mechanisms underlying the differentiation-promoting effects of Wnt5a on DA precursors are poorly understood. Here, we present the molecular and functional characterization of a signaling pathway downstream of Wnt5a, the Wnt/Dvl/Rac1 pathway. First, we characterize the interaction between Rac1 and Dvl and identify the N-terminal part of Dvl3 as necessary for Rac1 binding. Next, we show that Tiam1, a Rac1 guanosine exchange factor (GEF), is expressed in the ventral midbrain, interacts with Dvl, facilitates Dvl-Rac1 interaction, and is required for Dvl- or Wnt5a-induced activation of Rac1. Moreover, we show that Wnt5a promotes whereas casein kinase 1 (CK1), a negative regulator of the Wnt/Dvl/Rac1 pathway, abolishes the interactions between Dvl and Tiam1. Finally, using ventral midbrain neurosphere cultures, we demonstrate that the generation of DA neurons in culture is impaired after Tiam1 knockdown, indicating that Tiam1 is required for midbrain DA differentiation. In summary, our data identify Tiam1 as a novel regulator of DA neuron development and as a Dvl-associated and Rac1-specific GEF acting in the Wnt/Dvl/Rac1 pathway.
authors.affiliation: Molecular Neurobiology Unit, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Lukáš
authors.initials: L
authors.lastname: Čajánek
authors.forename: Ranjani Sri
authors.initials: RS
authors.lastname: Ganji
authors.forename: Catarina
authors.initials: C
authors.lastname: Henriques-Oliveira
authors.forename: Spyridon
authors.initials: S
authors.lastname: Theofilopoulos
authors.forename: Peter
authors.initials: P
authors.lastname: Koník
authors.forename: Vítězslav
authors.initials: V
authors.lastname: Bryja
authors.forename: Ernest
authors.initials: E
authors.lastname: Arenas
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D047389:Casein Kinase I / Q000378:metabolism; D002454:Cell Differentiation; D000072261:Dishevelled Proteins; D059290:Dopaminergic Neurons / Q000166:cytology* / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D051379:Mice; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D000071818:Wnt-5a Protein; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000606584:DVL3 protein, human; D000072261:Dishevelled Proteins; C000606585:Dvl3 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D009479:Neuropeptides; D010750:Phosphoproteins; C484602:Rac1 protein, mouse; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human; C513260:Tiam1 protein, mouse; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D047389:Casein Kinase I; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein