title: Neuronal differentiation of embryonic midbrain cells by upregulation of peroxisome proliferator-activated receptor-gamma via the JNK-dependent pathway.
abstract: 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.
authors.affiliation: National Institute of Toxicological Research, Korea Food and Drug Administration, Seoul, South Korea.
authors.forename: Ki Sook
authors.initials: KS
authors.lastname: Park
authors.forename: Rhee Da
authors.initials: RD
authors.lastname: Lee
authors.forename: Sun-Kyung
authors.initials: SK
authors.lastname: Kang
authors.forename: Soon Young
authors.initials: SY
authors.lastname: Han
authors.forename: Kui Lae
authors.initials: KL
authors.lastname: Park
authors.forename: Ki Hwa
authors.initials: KH
authors.lastname: Yang
authors.forename: Youn Sook
authors.initials: YS
authors.lastname: Song
authors.forename: Hye Ji
authors.initials: HJ
authors.lastname: Park
authors.forename: Yoot Mo
authors.initials: YM
authors.lastname: Lee
authors.forename: Yeo Pyo
authors.initials: YP
authors.lastname: Yun
authors.forename: Ki Wan
authors.initials: KW
authors.lastname: Oh
authors.forename: Dae Joong
authors.initials: DJ
authors.lastname: Kim
authors.forename: Young Won
authors.initials: YW
authors.lastname: Yun
authors.forename: Se Jin
authors.initials: SJ
authors.lastname: Hwang
authors.forename: Sung Eun
authors.initials: SE
authors.lastname: Lee
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
mesh_terms: 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
chemical_list: 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