Estrogen-related receptor gamma regulates dopaminergic neuronal phenotype by activating GSK3β/NFAT signaling in SH-SY5Y cells.
The orphan nuclear receptor estrogen-related receptor gamma (ERRγ) is highly expressed in the nervous system during embryogenesis and in adult brains, but its physiological role in neuronal development remains unknown. In this study, we evaluated the relevance of ERRγ in regulating dopaminergic (DAergic) phenotype and the corresponding signaling pathway. We used retinoic acid (RA) to differentiate human neuroblastoma SH-SY5Y cells. RA induced neurite outgrowth of SH-SY5Y cells with an increase in DAergic neuron-like properties, including up-regulation of tyrosine hydroxylase, dopamine transporter, and vesicular monoamine transporter 2. ERRγ, but not ERRα, was up-regulated by RA, and participated in RA effect on SH-SY5Y cells. ERRγ over-expression enhanced mature DAergic neuronal phenotype with neurite outgrowth as with RA treatment; and RA-induced increase in DAergic phenotype was attenuated by silencing ERRγ expression. ERRγ appears to have a crucial role in morphological and functional regulation of cells that is selective for DAergic neurons. Polo-like kinase 2 was up-regulated in ERRγ-over-expressing SH-SY5Y cells, which was involved in phosphorylation of glycogen synthase kinase 3β and resulting downstream activation of nuclear factor of activated T cells. The likely involvement of ERRγ in regulating the DAergic neuronal phenotype makes this orphan nuclear receptor a novel target for understanding DAergic neuronal differentiation. We propose the relevance of estrogen-related receptor gamma (ERRγ) in regulating dopaminergic neuronal phenotype: ERRγ is up-regulated by retinoic acid in SH-SY5Y cells, and enhances dopaminergic phenotypes and induces neurite outgrowth; Polo-like kinase 2 (PLK2) and glycogen synthase kinase 3 beta/nuclear factor of activated T cells (GSK3β/NFAT) signaling are responsible for the ERRγ effect. Our findings provide the first insights into the role of ERRγ in the brain, as a novel approach toward understanding dopaminergic differentiation.
College of Pharmacy, CHA University, Seongnam, Korea.
Juhee
J
Lim
Hueng-Sik
HS
Choi
Hyun Jin
HJ
Choi
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002458:Cell Fractionation; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
C490917:ESRRG protein, human; D050778:NFATC Transcription Factors; D009419:Nerve Tissue Proteins; D011960:Receptors, Estrogen; D014212:Tretinoin; D014446:Tyrosine 3-Monooxygenase; C496126:PLK2 protein, human; D017346:Protein Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3
ERRγ; GSK3β; dopamine transporter; dopaminergic neuron; neurite outgrowth; tyrosine hydroxylase