title: Foxa2 and Nurr1 synergistically yield A9 nigral dopamine neurons exhibiting improved differentiation, function, and cell survival.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Hanyang University, Seoul, Korea.
authors.forename: Hyun-Seob
authors.initials: HS
authors.lastname: Lee
authors.forename: Eun-Ji
authors.initials: EJ
authors.lastname: Bae
authors.forename: Sang-Hoon
authors.initials: SH
authors.lastname: Yi
authors.forename: Jae-Won
authors.initials: JW
authors.lastname: Shim
authors.forename: A-Young
authors.initials: AY
authors.lastname: Jo
authors.forename: Jin-Sun
authors.initials: JS
authors.lastname: Kang
authors.forename: Eun-Hye
authors.initials: EH
authors.lastname: Yoon
authors.forename: Yong-Hee
authors.initials: YH
authors.lastname: Rhee
authors.forename: Chang-Hwan
authors.initials: CH
authors.lastname: Park
authors.forename: Hyun-Chul
authors.initials: HC
authors.lastname: Koh
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
authors.forename: Jeung-Whan
authors.initials: JW
authors.lastname: Han
authors.forename: Yong-Sung
authors.initials: YS
authors.lastname: Lee
authors.forename: Jaesang
authors.initials: J
authors.lastname: Kim
authors.forename: Jia-Yi
authors.initials: JY
authors.lastname: Li
authors.forename: Patrik
authors.initials: P
authors.lastname: Brundin
authors.forename: Sang-Hun
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics*; D006801:Humans; D051379:Mice; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics*; D010300:Parkinson Disease / Q000601:surgery; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D013378:Substantia Nigra / Q000166:cytology / Q000378:metabolism; D014162:Transfection / Q000379:methods; D016896:Treatment Outcome
chemical_list: C496502:FOXA2 protein, human; C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D051542:Hepatocyte Nuclear Factor 3-beta; D004298:Dopamine