Dopaminergic neuronal differentiation from rat embryonic neural precursors by Nurr1 overexpression.
In vitro expanded CNS precursors could provide a renewable source of dopamine (DA) neurons for cell therapy in Parkinson's disease. Functional DA neurons have been derived previously from early midbrain precursors. Here we demonstrate the ability of Nurr1, a nuclear orphan receptor essential for midbrain DA neuron development in vivo, to induce dopaminergic differentiation in naïve CNS precursors in vitro. Independent of gestational age or brain region of origin, Nurr1-induced precursors expressed dopaminergic markers and exhibited depolarization-evoked DA release in vitro. However, these cells were less mature and secreted lower levels of DA than those derived from mesencephalic precursors. Transplantation of Nurr1-induced DA neuron precursors resulted in limited survival and in vivo differentiation. No behavioral improvement in apomorphine-induced rotation scores was observed. These results demonstrate that Nurr1 induces dopaminergic features in naïve CNS precursors in vitro. However, additional factors will be required to achieve in vivo function and to unravel the full potential of neural precursors for cell therapy in Parkinson's disease.
Kim
Ju-Yeon
JY
Department of Biochemistry, and Institute of Mental Health, Hanyang University, Seoul, Korea.
Koh
Hyun Chul
HC
Lee
Ji-Yeon
JY
Chang
Mi-Yoon
MY
Kim
You-Chan
YC
Chung
Hee-Yong
HY
Son
Hyeon
H
Lee
Yong-Sung
YS
Studer
Lorenz
L
McKay
Ron
R
Lee
Sang-Hun
SH
D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D001058:Apomorphine / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D015870:Gene Expression; D005865:Gestational Age; D006085:Graft Survival; D008297:Male; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012190:Retroviridae / Q000235:genetics; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D014161:Transduction, Genetic; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis
D000943:Antigens, Differentiation; D004268:DNA-Binding Proteins; C539884:Nr4a2 protein, rat; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D014157:Transcription Factors; D014446:Tyrosine 3-Monooxygenase; D001058:Apomorphine; D001205:Ascorbic Acid; D004298:Dopamine