GSK-3β inhibition/β-catenin stabilization in ventral midbrain precursors increases differentiation into dopamine neurons
GSK-3β inhibition/β-catenin stabilization in ventral midbrain precursors increases differentiation into dopamine neurons
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DOI：
10.1242/jcs.01505
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发表时间：
2004-11-15
影响因子：
4
通讯作者：
Arenas, E
中科院分区：
文献类型：
--
作者：
Castelo-Branco, G;Rawal, N;Arenas, E
Wnt是发育中中脑腹侧多巴胺（DA）神经元分化的重要调节因子，因此可以作为治疗帕金森病的潜在工具。在这项研究中，我们调查是否建立细胞内Wnt信号成分可以调节DA神经元的发展。发现糖原合成酶激酶（GSK）-3 β的两种化学抑制剂靛玉红-3-单肟和kenpaullone可增加腹侧中脑前体培养物中的神经元分化。此外，GSK-3 β特异性抑制剂kenpaullone通过将表达孤儿核受体相关因子1的前体转化为酪氨酸羟化酶阳性神经元来增加DA神经元群体的大小，从而模拟Wnt的作用。我们发现，GSK-3 β抑制剂稳定β-连环蛋白和腹侧中脑前体中β-连环蛋白的过度表达导致DA分化增加。GSK-3 β抑制剂使前体细胞的DA分化增加3至5倍，表明此类化合物可用于改善帕金森病的干细胞/前体细胞治疗方法。
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.