Foxa2 and Nurr1 synergistically yield A9 nigral dopamine neurons exhibiting improved differentiation, function, and cell survival.
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.
Lee
Hyun-Seob
HS
Department of Biochemistry and Molecular Biology, Hanyang University, Seoul, Korea.
Bae
Eun-Ji
EJ
Yi
Sang-Hoon
SH
Shim
Jae-Won
JW
Jo
A-Young
AY
Kang
Jin-Sun
JS
Yoon
Eun-Hye
EH
Rhee
Yong-Hee
YH
Park
Chang-Hwan
CH
Koh
Hyun-Chul
HC
Kim
Hyun-Jung
HJ
Choi
Hueng-Sik
HS
Han
Jeung-Whan
JW
Lee
Yong-Sung
YS
Kim
Jaesang
J
Li
Jia-Yi
JY
Brundin
Patrik
P
Lee
Sang-Hun
SH
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
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