AUTHOR=Göcz Balázs , Takács Szabolcs , Skrapits Katalin , Rumpler Éva , Solymosi Norbert , Póliska Szilárd , Colledge William H. , Hrabovszky Erik , Sárvári Miklós 

TITLE=Estrogen differentially regulates transcriptional landscapes of preoptic and arcuate kisspeptin neuron populations

JOURNAL=Frontiers in Endocrinology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.960769

DOI=10.3389/fendo.2022.960769

ISSN=1664-2392

ABSTRACT=<p>Kisspeptin neurons residing in the rostral periventricular area of the third ventricle (KP<sup>RP3V</sup>) and the arcuate nucleus (KP<sup>ARC</sup>) mediate positive and negative estrogen feedback, respectively. Here, we aim to compare transcriptional responses of KP<sup>RP3V</sup> and KP<sup>ARC</sup> neurons to estrogen. Transgenic mice were ovariectomized and supplemented with either 17β-estradiol (E2) or vehicle. Fluorescently tagged KP<sup>RP3V</sup> neurons collected by laser-capture microdissection were subjected to RNA-seq. Bioinformatics identified 222 E2-dependent genes. Four genes encoding neuropeptide precursors (<italic>Nmb, Kiss1, Nts, Penk</italic>) were robustly, and <italic>Cartpt</italic> was subsignificantly upregulated, suggesting putative contribution of multiple neuropeptides to estrogen feedback mechanisms. Using overrepresentation analysis, the most affected KEGG pathways were neuroactive ligand-receptor interaction and dopaminergic synapse. Next, we re-analyzed our previously obtained KP<sup>ARC</sup> neuron RNA-seq data from the same animals using identical bioinformatic criteria. The identified 1583 E2-induced changes included suppression of many neuropeptide precursors, granins, protein processing enzymes, and other genes related to the secretory pathway. In addition to distinct regulatory responses, KP<sup>RP3V</sup> and KP<sup>ARC</sup> neurons exhibited sixty-two common changes in genes encoding three hormone receptors (<italic>Ghsr, Pgr, Npr2</italic>), GAD-65 (<italic>Gad2</italic>), calmodulin and its regulator (<italic>Calm1, Pcp4</italic>), among others. Thirty-four oppositely regulated genes (<italic>Kiss1, Vgf, Chrna7, Tmem35a</italic>) were also identified. The strikingly different transcriptional responses in the two neuron populations prompted us to explore the transcriptional mechanism further. We identified ten E2-dependent transcription factors in KP<sup>RP3V</sup> and seventy in KP<sup>ARC</sup> neurons. While none of the ten transcription factors interacted with estrogen receptor-α, eight of the seventy did. We propose that an intricate, multi-layered transcriptional mechanism exists in KP<sup>ARC</sup> neurons and a less complex one in KP<sup>RP3V</sup> neurons. These results shed new light on the complexity of estrogen-dependent regulatory mechanisms acting in the two functionally distinct kisspeptin neuron populations and implicate additional neuropeptides and mechanisms in estrogen feedback.</p>