Wnt1-Imx1a Forms a Novel Autoregulatory Loop and Controls Midbrain Dopaminergic Differentiation Synergistically with the SHH-FoxA2 Pathway

被引:160
作者
Chung, Sangmi [1 ,2 ,3 ]
Leung, Amanda [1 ,2 ,3 ]
Han, Baek-Soo [1 ,2 ,3 ]
Chang, Mi-Yoon [1 ,2 ,3 ]
Moon, Jung-Il [1 ,2 ,3 ]
Kim, Chun-Hyung [1 ,2 ,3 ]
Hong, Sunghoi [1 ,2 ,3 ]
Pruszak, Jan [3 ,4 ]
Isacson, Ole [3 ,4 ]
Kim, Kwang-Soo [1 ,2 ,3 ]
机构
[1] Harvard Univ, McLean Hosp, Sch Med, Dept Psychiat,Mol Neurobiol Lab, Belmont, MA 02478 USA
[2] Harvard Univ, McLean Hosp, Sch Med, Program Neurosci, Belmont, MA 02478 USA
[3] Harvard Univ, McLean Hosp, Sch Med, Harvard Stem Cell Inst, Belmont, MA 02478 USA
[4] Harvard Univ, McLean Hosp, Sch Med, Neurogenerat Labs, Belmont, MA 02478 USA
关键词
EMBRYONIC STEM-CELLS; FLOOR PLATE; PARKINSONS-DISEASE; NEURON DEVELOPMENT; ISTHMIC ORGANIZER; SONIC HEDGEHOG; BETA-CATENIN; FGF8; HINDBRAIN; GROWTH;
D O I
10.1016/j.stem.2009.09.015
中图分类号
Q813 [细胞工程];
学科分类号
摘要
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.
引用
收藏
页码:646 / 658
页数:13
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