Tiam1 regulates the Wnt/Dvl/Rac1 signaling pathway and the differentiation of midbrain dopaminergic neurons.

ČAJÁNEK, Lukáš, Sri Ranjani GANJI, Catarina HENRIQUES-OLIVIA, Spyridon THEOFILOPOULOS, Peter KONÍK, Vítězslav BRYJA and Ernest ARENAS. Tiam1 regulates the Wnt/Dvl/Rac1 signaling pathway and the differentiation of midbrain dopaminergic neurons. Molecular and cellular biology. 2013, vol. 33, No 1, p. 59-70. ISSN 0270-7306. Available from: https://dx.doi.org/10.1128/MCB.00745-12.

Basic information

• Original name: Tiam1 regulates the Wnt/Dvl/Rac1 signaling pathway and the differentiation of midbrain dopaminergic neurons.
• Authors: ČAJÁNEK, Lukáš (203 Czech Republic), Sri Ranjani GANJI (356 India, belonging to the institution), Catarina HENRIQUES-OLIVIA (752 Sweden), Spyridon THEOFILOPOULOS (300 Greece), Peter KONÍK (703 Slovakia), Vítězslav BRYJA (203 Czech Republic, guarantor, belonging to the institution) and Ernest ARENAS (724 Spain).
• Edition: Molecular and cellular biology, 2013, 0270-7306.

Other information

• Original language: English
• Type of outcome: Article in a journal
• Field of Study: 30105 Physiology
• Country of publisher: United States of America
• Confidentiality degree: is not subject to a state or trade secret
• Impact factor: Impact factor: 5.036
• RIV identification code: RIV/00216224:14310/13:00066065
• Organization unit: Faculty of Science
• Doi: http://dx.doi.org/10.1128/MCB.00745-12
• UT WoS: 000317184200007
• Keywords in English: Wnt; Dvl; Rac1; Tiam1
• Tags: AKR, rivok, ZR

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.

Links

• EE2.3.20.0180, research and development project: Name: Spolupráce mezi Masarykovou univerzitou a Karolinska Institutet, Stockholm na poli biomedicíny
• GA204/09/0498, research and development project: Name: Dynamika proteinů interagujících s Dishevelled a jejich význam pro Wnt signálování

Investor: Czech Science Foundation, Dynamics of proteins interacting with Dishevelled and their importance for Wnt signalling

• GD204/09/H058, research and development project: Name: Mezibuněčná signalizace ve vývoji organismu a vzniku onemocnění

Investor: Czech Science Foundation, Intercellular signalling in development and disease

• MSM0021622430, plan (intention): Name: Funkční a molekulární charakteristiky nádorových a normálních kmenových buněk - identifikace cílů pro nová terapeutika a terapeutické strategie

Investor: Ministry of Education, Youth and Sports of the CR, Functional and molecular characteristics of cancer and normal stem cells - identification of targets for novel therapeutics and therapeutic strategies