AUTHOR=Vastagh Csaba , Csillag Veronika , Solymosi Norbert , Farkas Imre , Liposits Zsolt 

TITLE=Gonadal Cycle-Dependent Expression of Genes Encoding Peptide-, Growth Factor-, and Orphan G-Protein-Coupled Receptors in Gonadotropin- Releasing Hormone Neurons of Mice

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=13

YEAR=2021

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2020.594119

DOI=10.3389/fnmol.2020.594119

ISSN=1662-5099

ABSTRACT=<p>Rising serum estradiol triggers the surge release of gonadotropin-releasing hormone (GnRH) at late proestrus leading to ovulation. We hypothesized that proestrus evokes alterations in peptidergic signaling onto GnRH neurons inducing a differential expression of neuropeptide-, growth factor-, and orphan G-protein-coupled receptor (GPCR) genes. Thus, we analyzed the transcriptome of GnRH neurons collected from intact, proestrous and metestrous GnRH-green fluorescent protein (GnRH-GFP) transgenic mice using Affymetrix microarray technique. Proestrus resulted in a differential expression of genes coding for peptide/neuropeptide receptors including <italic>Adipor1, Prokr1, Ednrb, Rtn4r, Nmbr, Acvr2b, Sctr, Npr3, Nmur1, Mc3r, Cckbr</italic>, and <italic>Amhr2</italic>. In this gene cluster, <italic>Adipor1</italic> mRNA expression was upregulated and the others were downregulated. Expression of growth factor receptors and their related proteins was also altered showing upregulation of <italic>Fgfr1, Igf1r, Grb2, Grb10</italic>, and <italic>Ngfrap1</italic> and downregulation of <italic>Egfr</italic> and <italic>Tgfbr2</italic> genes. <italic>Gpr107</italic>, an orphan GPCR, was upregulated during proestrus, while others were significantly downregulated (<italic>Gpr1, Gpr87, Gpr18, Gpr62, Gpr125, Gpr183, Gpr4</italic>, and <italic>Gpr88</italic>). Further affected receptors included vomeronasal receptors (<italic>Vmn1r172, Vmn2r-ps54</italic>, and <italic>Vmn1r148</italic>) and platelet-activating factor receptor (<italic>Ptafr</italic>), all with marked downregulation. Patch-clamp recordings from mouse GnRH-GFP neurons carried out at metestrus confirmed that the differentially expressed IGF-1, secretin, and GPR107 receptors were operational, as their activation by specific ligands evoked an increase in the frequency of miniature postsynaptic currents (mPSCs). These findings show the contribution of certain novel peptides, growth factors, and ligands of orphan GPCRs to regulation of GnRH neurons and their preparation for the surge release.</p>