Tiam1 Regulates the Wnt/Dvl/Rac1 Signaling Pathway and the Differentiation of Midbrain Dopaminergic Neurons
Tiam1 Regulates the Wnt/Dvl/Rac1 Signaling Pathway and the Differentiation of Midbrain Dopaminergic Neurons
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DOI：
10.1128/mcb.00745-12
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发表时间：
2013-01-01
影响因子：
5.3
通讯作者：
Arenas, Ernest
中科院分区：
文献类型：
--
作者：
Cajanek, Lukas;Ganji, Ranjani Sri;Arenas, Ernest
了解多巴胺能（DA）神经元分化的驱动机制对于成功开发帕金森病的新疗法至关重要，其中DA神经元进行性退化。然而，Wnt 5a对DA前体的分化促进作用的机制知之甚少。在这里，我们提出了Wnt 5a下游的信号通路，Wnt/Dvl/Rac 1通路的分子和功能特性。首先，我们表征了Rac 1和Dvl之间的相互作用，并确定了Rac 1结合所必需的Dvl 3的N-末端部分。接下来，我们表明，Tiam 1，一个Rac 1鸟苷交换因子（GEF），在腹侧中脑中表达，与Dvl相互作用，促进Dvl-Rac 1相互作用，并需要Dvl或Wnt 5a诱导的Rac 1激活。此外，我们表明，Wnt 5a促进，而酪蛋白激酶1（CK 1），Wnt/Dvl/Rac 1途径的负调节，取消Dvl和Tiam 1之间的相互作用。最后，使用腹侧中脑神经球文化，我们证明，在文化中的DA神经元的产生受损后Tiam 1敲低，表明Tiam 1是必需的中脑DA分化。总之，我们的数据确定Tiam 1作为DA神经元发育的新调节剂，并且作为Dvl相关和Rac 1特异性GEF在Wnt/Dvl/Rac 1通路中起作用。
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.