Department of Psychiatry and Program in Neuroscience, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
Cell Stem Cell. 2009 Dec 4;5(6):646-58. doi: 10.1016/j.stem.2009.09.015.
Selective degeneration of midbrain dopaminergic (mDA) neurons is associated with Parkinson's disease (PD), and thus an in-depth understanding of molecular pathways underlying mDA development will be crucial for optimal bioassays and cell replacement therapy for PD. In this study, we identified a novel Wnt1-Lmx1a autoregulatory loop during mDA differentiation of ESCs and confirmed its in vivo presence during embryonic development. We found that the Wnt1-Lmx1a autoregulatory loop directly regulates Otx2 through the beta-catenin complex and Nurr1 and Pitx3 through Lmx1a. We also found that Lmx1a and Lmx1b cooperatively regulate mDA differentiation with overlapping and cross-regulatory functions. Furthermore, coactivation of both Wnt1 and SHH pathways by exogenous expression of Lmx1a, Otx2, and FoxA2 synergistically enhanced the differentiation of ESCs to mDA neurons. Together with previous works, this study shows that two regulatory loops (Wnt1-Lmx1a and SHH-FoxA2) critically link extrinsic signals to cell-intrinsic factors and cooperatively regulate mDA neuron development.
中脑多巴胺能（mDA）神经元的选择性退化与帕金森病（PD）有关，因此深入了解 mDA 发育的分子途径对于 PD 的最佳生物测定和细胞替代疗法至关重要。在这项研究中，我们在 ESC 的 mDA 分化过程中鉴定出了一个新的 Wnt1-Lmx1a 自身调节回路，并在胚胎发育过程中证实了其体内存在。我们发现 Wnt1-Lmx1a 自身调节回路通过β-连环蛋白复合物和 Lmx1a 直接调节 Otx2 和 Nurr1 和 Pitx3。我们还发现 Lmx1a 和 Lmx1b 以重叠和交叉调节功能共同调节 mDA 分化。此外，通过外源性表达 Lmx1a、Otx2 和 FoxA2 共同激活 Wnt1 和 SHH 通路，协同增强了 ESC 向 mDA 神经元的分化。结合以前的工作，这项研究表明两个调节回路（Wnt1-Lmx1a 和 SHH-FoxA2）将外源性信号与细胞内在因素紧密联系起来，并协同调节 mDA 神经元的发育。
