Glucocorticoid receptor-mediated regulation of Rfrp (GnIH) and Gpr147 (GnIH-R) synthesis in immortalized hypothalamic neurons

• Novel hypothalamic cell line expressing GnIH (Rfrp-3) and GnIH-R (GPR147).
• Glucocorticoid (GC) dexamethasone regulates both GnIH and GnIH-R.
• Nuclear GC receptor mediates GC-dependent transcriptional changes.
• GC-mediated changes independent of de novo protein synthesis.
• Estrogen does not directly regulate the mRNA for these genes.

A novel RFamide peptide, gonadotropin-inhibitory hormone (GnIH) has emerged as a modulator of avian reproduction. However, the functional role of the mammalian homologue, RFRP-3 remains poorly understood. The RFRP-3 neuronal circuit is influenced by the stress axis. However, whether the Rfrp gene is under direct glucocorticoid (GC)-mediated transcriptional regulation, in the presence and absence of the gonadal steroid, 17β-estradiol, is unknown. We investigated the regulation of the Rfrp (GnIH) and Gpr147 (GnIH-R) transcripts by steroids in a novel hypothalamic Rfrp-expressing cell model, rHypoE-23. The GC agonist, dexamethasone increased Rfrp and Gpr147 mRNA levels. Dexamethasone acted directly on the nuclear GC receptor (GR) to mediate GC-dependent transcriptional changes, independently of de novo protein synthesis. 17β-estradiol had no significant effect on Rfrp or Gpr147 biosynthesis in these neurons. This suggests that Rfrp-expressing neurons serve as potential upstream mediators of stress-induced effects through GR-dependent mechanisms.

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