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Estrogen‐related receptor gamma regulates dopaminergic neuronal phenotype by activating GSK 3β/ NFAT signaling in SH ‐ SY 5Y cells
Author(s) -
Lim Juhee,
Choi HuengSik,
Choi Hyun Jin
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13085
Subject(s) - neurite , microbiology and biotechnology , dopaminergic , biology , nuclear receptor , orphan receptor , estrogen receptor , retinoic acid , tyrosine hydroxylase , chemistry , dopamine , transcription factor , endocrinology , biochemistry , genetics , cancer , breast cancer , gene , in vitro
The orphan nuclear receptor estrogen‐related receptor gamma ( ERR γ) 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 ERR γ in regulating dopaminergic ( DA ergic) phenotype and the corresponding signaling pathway. We used retinoic acid ( RA ) to differentiate human neuroblastoma SH ‐ SY 5Y cells. RA induced neurite outgrowth of SH ‐ SY 5Y cells with an increase in DA ergic neuron‐like properties, including up‐regulation of tyrosine hydroxylase, dopamine transporter, and vesicular monoamine transporter 2. ERR γ, but not ERR α, was up‐regulated by RA , and participated in RA effect on SH ‐ SY 5Y cells. ERR γ over‐expression enhanced mature DA ergic neuronal phenotype with neurite outgrowth as with RA treatment; and RA ‐induced increase in DA ergic phenotype was attenuated by silencing ERR γ expression. ERR γ appears to have a crucial role in morphological and functional regulation of cells that is selective for DA ergic neurons. Polo‐like kinase 2 was up‐regulated in ERR γ‐over‐expressing SH ‐ SY 5Y 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 ERR γ in regulating the DA ergic neuronal phenotype makes this orphan nuclear receptor a novel target for understanding DA ergic 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.