Hypoxia-inducible factor-1α upregulates tyrosine hydroxylase and dopamine transporter by nuclear receptor ERRγ in SH-SY5Y cells.

Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a transcription factor relevant to the development of many mammalian organs including the brain. However, the molecular mechanisms by which signaling events mediate neuronal differentiation have not been fully elucidated. In the present study, we show for the first time that the orphan nuclear receptor estrogen-related receptor gamma (ERR gamma) is upregulated by HIF-1 alpha and plays essential roles in HIF-1 alpha-induced upregulation of dopaminergic marker molecules such as tyrosine hydroxylase and dopamine transporter. We found that deferoxamine upregulated HIF-1 alpha and enhanced the dopaminergic phenotype and neurite outgrowth of SH-SY5Y cells. Deferoxamine activated transcription and protein expression of ERR gamma, and deferoxamine-induced upregulation of tyrosine hydroxylase and dopamine transporter was attenuated by using the ERR gamma inverse agonist or silencing ERR gamma. Altogether, these results suggest that HIF-1 alpha can positively regulate the dopaminergic phenotype through ERR gamma. This study could provide new perspectives for understanding the mechanisms underlying the promotion of dopaminergic neuronal differentiation by hypoxia. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved.