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Foxa2 and Nurr1 Synergistically Yield A9 Nigral Dopamine Neurons Exhibiting Improved Differentiation, Function, and Cell Survival

Lee, Hyun-Seob; Bae, Eun-Ji; Yi, Sang-Hoon; Shim, Jae-Won; Jo, A-Young; Kang, Jin-Sun; Yoon, Eun-Hye; Rhee, Yong-Hee; Park, Chang-Hwan and Koh, Hyun-Chul, et al. (2010) In Stem Cells 28(3). p.501-512
Abstract
Effective dopamine (DA) neuron differentiation from neural precursor cells (NPCs) is prerequisite for precursor/stem cell-based therapy of Parkinson's disease (PD). Nurr1, an orphan nuclear receptor, has been reported as a transcription factor that can drive DA neuron differentiation from non-dopaminergic NPCs in vitro. However, Nurr1 alone neither induces full neuronal maturation nor expression of proteins found specifically in midbrain DA neurons. In addition, Nurr1 expression is inefficient in inducing DA phenotype expression in NPCs derived from certain species such as mouse and human. We show here that Foxa2, a forkhead transcription factor whose role in midbrain DA neuron development was recently revealed, synergistically cooperates... (More)
Effective dopamine (DA) neuron differentiation from neural precursor cells (NPCs) is prerequisite for precursor/stem cell-based therapy of Parkinson's disease (PD). Nurr1, an orphan nuclear receptor, has been reported as a transcription factor that can drive DA neuron differentiation from non-dopaminergic NPCs in vitro. However, Nurr1 alone neither induces full neuronal maturation nor expression of proteins found specifically in midbrain DA neurons. In addition, Nurr1 expression is inefficient in inducing DA phenotype expression in NPCs derived from certain species such as mouse and human. We show here that Foxa2, a forkhead transcription factor whose role in midbrain DA neuron development was recently revealed, synergistically cooperates with Nurr1 to induce DA phenotype acquisition, midbrain-specific gene expression, and neuronal maturation. Thus, the combinatorial expression of Nurr1 and Foxa2 in NPCs efficiently yielded fully differentiated nigral (A9)-type midbrain neurons with clearly detectable DA neuronal activities. The effects of Foxa2 in DA neuron generation were observed regardless of the brain regions or species from which NPCs were derived. Furthermore, DA neurons generated by ectopic Foxa2 expression were more resistant to toxins. Importantly, Foxa2 expression resulted in a rapid cell cycle exit and reduced cell proliferation. Consistently, transplantation of NPCs transduced with Nurr1 and Foxa2 generated grafts enriched with midbrain-type DA neurons but reduced number of proliferating cells, and significantly reversed motor deficits in a rat PD model. Our findings can be applied to ongoing attempts to develop an efficient and safe precursor/stem cell-based therapy for PD. STEM CELLS 2010; 28: 501-512 (Less)
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keywords
Nurr1, Foxa2, Dopamine neurons, Neural precursor cells, Parkinson's, Cell transplantation, disease
in
Stem Cells
volume
28
issue
3
pages
501 - 512
publisher
AlphaMed Press
external identifiers
  • wos:000277093700013
  • scopus:77950552036
ISSN
1549-4918
DOI
10.1002/stem.294
language
English
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yes
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67f9f6dc-e565-4e26-bb2b-fe15fda8f6c6 (old id 1618993)
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2010-06-18 14:15:24
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2018-05-29 11:20:51
@article{67f9f6dc-e565-4e26-bb2b-fe15fda8f6c6,
  abstract     = {Effective dopamine (DA) neuron differentiation from neural precursor cells (NPCs) is prerequisite for precursor/stem cell-based therapy of Parkinson's disease (PD). Nurr1, an orphan nuclear receptor, has been reported as a transcription factor that can drive DA neuron differentiation from non-dopaminergic NPCs in vitro. However, Nurr1 alone neither induces full neuronal maturation nor expression of proteins found specifically in midbrain DA neurons. In addition, Nurr1 expression is inefficient in inducing DA phenotype expression in NPCs derived from certain species such as mouse and human. We show here that Foxa2, a forkhead transcription factor whose role in midbrain DA neuron development was recently revealed, synergistically cooperates with Nurr1 to induce DA phenotype acquisition, midbrain-specific gene expression, and neuronal maturation. Thus, the combinatorial expression of Nurr1 and Foxa2 in NPCs efficiently yielded fully differentiated nigral (A9)-type midbrain neurons with clearly detectable DA neuronal activities. The effects of Foxa2 in DA neuron generation were observed regardless of the brain regions or species from which NPCs were derived. Furthermore, DA neurons generated by ectopic Foxa2 expression were more resistant to toxins. Importantly, Foxa2 expression resulted in a rapid cell cycle exit and reduced cell proliferation. Consistently, transplantation of NPCs transduced with Nurr1 and Foxa2 generated grafts enriched with midbrain-type DA neurons but reduced number of proliferating cells, and significantly reversed motor deficits in a rat PD model. Our findings can be applied to ongoing attempts to develop an efficient and safe precursor/stem cell-based therapy for PD. STEM CELLS 2010; 28: 501-512},
  author       = {Lee, Hyun-Seob and Bae, Eun-Ji and Yi, Sang-Hoon and Shim, Jae-Won and Jo, A-Young and Kang, Jin-Sun and Yoon, Eun-Hye and Rhee, Yong-Hee and Park, Chang-Hwan and Koh, Hyun-Chul and Kim, Hyun-Jung and Choi, Hueng-Sik and Han, Jeung-Whan and Lee, Yong-Sung and Kim, Jaesang and Li, Jia-Yi and Brundin, Patrik and Lee, Sang-Hun},
  issn         = {1549-4918},
  keyword      = {Nurr1,Foxa2,Dopamine neurons,Neural precursor cells,Parkinson's,Cell transplantation,disease},
  language     = {eng},
  number       = {3},
  pages        = {501--512},
  publisher    = {AlphaMed Press},
  series       = {Stem Cells},
  title        = {Foxa2 and Nurr1 Synergistically Yield A9 Nigral Dopamine Neurons Exhibiting Improved Differentiation, Function, and Cell Survival},
  url          = {http://dx.doi.org/10.1002/stem.294},
  volume       = {28},
  year         = {2010},
}