Neuronal differentiation of embryonic midbrain cells by upregulation of peroxisome proliferator-activated receptor-gamma via the JNK-dependent pathway.
Our previous study showed that the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist 15-deoxy-PGJ(2) has the promoting ability to differentiate neuronal PC12 cells. To expand our study, the effect of 15-deoxy-PGJ(2) on the differentiation of embryonic midbrain cells into dopaminergic neuronal cells was investigated in this study. The relationship between cell differentiation with activation of PPAR-gamma and the possible signal pathway were also investigated. 15-Deoxy-PGJ(2) increased neurite extension, a typical characteristic of the differentiation of embryonic midbrain cells isolated from 12-day rat embryos in a dose-dependent manner. The expression of differentiation markers, neurofilament, tyrosine hydroxylase, and nestin, was also increased by the treatment of 15-deoxy-PGJ(2). Consistent with the increasing effect on cell differentiation, 15-deoxy-PGJ(2) increased the expression and transcriptional activity of PPAR-gamma in cultured embryonic midbrain cells. In addition, the expression of PPAR-gamma and NeuN in the differentiated neuron of fetus (17 days) and adult rat brain was co-localized. Furthermore, treatment of PPAR-gamma antagonist bisphenol A diglycidyl ether blocked 15-deoxy-PGJ(2)-induced neuronal differentiation of embryonic midbrain cells and expression of PPAR-gamma. To elucidate the possible signal pathway, the activation of mitogenic-activated protein (MAP) kinase family was determined. 15-Deoxy-PGJ(2) (0.5 microM) increased activation of Jun N-terminal kinase (JNK) and p38 kinase but not extra-signal response kinase (ERK). In addition, NGF (50 ng/ml) further increased the 15-deoxy-PGJ(2)-induced JNK activation. Moreover, pretreatment of specific inhibitor of JNK SP600125 blocked the 15-deoxy-PGJ(2)-induced JNK activation. This inhibition correlated well with the inhibition of neurite extension and expression of PPAR-gamma induced by 15-deoxy-PGJ(2). The present results therefore indicate that 15-deoxy-PGJ(2) stimulates differentiation of embryonic midbrain cells into dopaminergic neuronal cells, and its effect may be PPAR-gamma and JNK signal pathway dependent.
Park
Ki Sook
KS
National Institute of Toxicological Research, Korea Food and Drug Administration, Seoul, South Korea.
Lee
Rhee Da
RD
Kang
Sun-Kyung
SK
Han
Soon Young
SY
Park
Kui Lae
KL
Yang
Ki Hwa
KH
Song
Youn Sook
YS
Park
Hye Ji
HJ
Lee
Yoot Mo
YM
Yun
Yeo Pyo
YP
Oh
Ki Wan
KW
Kim
Dae Joong
DJ
Yun
Young Won
YW
Hwang
Se Jin
SJ
Lee
Sung Eun
SE
Hong
Jin Tae
JT
D000818:Animals; D001559:Benzhydryl Compounds; D002454:Cell Differentiation; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D007155:Immunologic Factors / Q000494:pharmacology; D007700:Kinetics; D008636:Mesencephalon / Q000166:cytology; D020932:Nerve Growth Factor / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D010636:Phenols / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D007155:Immunologic Factors; D020932:Nerve Growth Factor; D010636:Phenols; D015230:Prostaglandin D2; D016755:Proto-Oncogene Proteins c-jun; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C097240:15-deoxy-delta(12,14)-prostaglandin J2; C006780:bisphenol A; D000098826:Bisphenol A Compounds