Multiple roles of β-catenin in controlling the neurogenic niche for midbrain dopamine neurons
Multiple roles of β-catenin in controlling the neurogenic niche for midbrain dopamine neurons
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DOI：
10.1242/dev.034330
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发表时间：
2009-06-15
期刊：
影响因子：
4.6
通讯作者：
Huang, Eric J.
中科院分区：
文献类型：
--
作者：
Tang, Mianzhi;Miyamoto, Yasunori;Huang, Eric J.
基于干细胞的替代疗法已成为缓解帕金森病运动障碍特定特征的潜在策略。然而，目前从胚胎干细胞产生多巴胺（DA）神经元的策略有许多局限性，包括难以以高产量产生DA神经元。进一步了解控制DA神经元神经发生的机制将减少或减轻这种限制。腹侧中脑（vMB）包含产生DA神经元的神经原性小生境。然而，目前还不清楚这个生态位内的微环境如何控制DA神经发生。在这里，我们表明，β-连环蛋白控制DA神经元通过维持完整的神经原性生态位和从祖细胞到DA神经元的进展。使用条件性基因靶向方法，我们表明，区域缺失β-连环蛋白在vMB通过使用Shh-Cre破坏粘附连接的祖细胞和放射状胶质细胞的完整性，在vMB，这导致严重减少DA神经发生和扰乱DA神经元的迁移和分离。相比之下，Th-IRES-Cre去除神经祖细胞亚群中的β-连环蛋白，而不干扰vMB的细胞和结构完整性。有趣的是，Th-IRES-Cre; β-Ctn（fl/fl）突变体中β-连环蛋白的缺失通过干扰定向祖细胞向DA神经元的进展来负调节神经发生。总之，这些结果提供了新的见解β-连环蛋白在DA神经发生的多个阶段的不可或缺的功能。他们还表明，β-连环蛋白介导的信号通路可以在基于细胞的治疗策略中靶向促进和扩增DA神经元。发展
Stem cell-based replacement therapy has emerged as a potential strategy to alleviate specific features of movement disorder in Parkinson's disease. However, the current strategy to produce dopamine (DA) neurons from embryonic stem cells has many limitations, including the difficulty of generating DA neurons with high yields. Further insights into the mechanisms that control the neurogenesis of DA neurons will reduce or mitigate such limitations. It is well established that the ventral midbrain (vMB) contains the neurogenic niche that produces DA neurons. However, it is unclear how the microenvironment within this niche controls DA neurogenesis. Here, we show that beta-catenin controls DA neurogenesis by maintaining the integrity of the neurogenic niche and the progression from progenitors to DA neurons. Using conditional gene targeting approaches, we show that regional deletion of beta-catenin in the vMB by using Shh-Cre disrupts adherent junctions of progenitors and the integrity of radial glia in the vMB, which leads to a severe reduction in DA neurogenesis and perturbs the migration and segregation of DA neurons. By contrast, Th-IRES-Cre removes beta-catenin in a subset of neural progenitor cells without perturbing the cellular and structural integrity of the vMB. Interestingly, loss of beta-catenin in Th-IRES-Cre; beta-Ctn(fl/fl) mutants negatively regulates neurogenesis by interfering with the progression of committed progenitors to DA neurons. Taken together, these results provide new insights into the indispensable functions of beta-catenin at multiple stages during DA neurogenesis. They also suggest that beta-catenin-mediated signaling pathways can be targeted to promote and expand DA neurons in cell-based therapeutic strategies. DEVELOPMENT