Foxa2 and Nurr1 synergistically yield A9 nigral dopamine neurons exhibiting improved differentiation, function, and cell survival

Hyun Seo Lee, Eun Ji Bae, Sang Hoon Yi, Jae Won Shim, A. Young Jo, Jin Sun Kang, Eun Hye Yoon, Yong Hee Rhee, Chang Hwan Park, Hyun Chul Koh, Hyun Jung Kim, Hueng Sik Choi, Jeung Whan Han, Yong Sung Lee, Jaesang Kim, Jia Yi Li, Patrik Brundin, Sang Hun Lee

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

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 pheno-type 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.

Original languageEnglish
Pages (from-to)501-512
Number of pages12
JournalStem Cells
Volume28
Issue number3
DOIs
StatePublished - 31 Mar 2010

Keywords

  • Cell transplantation
  • Dopamine neurons
  • Foxa2
  • Neural precursor cells
  • Nurr1
  • Parkinson's disease

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