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Transcriptomic profiling reveals AVP-responsive molecular changes in GT1-7 GnRH neurons

ABSTRACT: Arginine vasopressin (AVP) has been implicated in the regulation of gonadotropin-releasing hormone (GnRH) neurons, but the transcriptomic mechanisms underlying this effect remain unclear. In this study, GT1-7 GnRH neuronal cells were treated with AVP and analyzed by bulk RNA sequencing. Compared with control cells, AVP treatment induced broad transcriptional changes, with 1,094 differentially expressed genes identified, including 549 up-regulated and 545 down-regulated genes. Functional enrichment analysis highlighted AVP-associated changes in signaling pathways related to TNF signaling, PI3K-Akt signaling, MAPK signaling, cAMP signaling, axon guidance, and Wnt signaling. These data provide a transcriptomic resource for understanding AVP-responsive molecular programs in GT1-7 GnRH neurons.

ORGANISM(S): Mus musculus

PROVIDER: GSE329856 | GEO | 2026/06/23

REPOSITORIES: GEO

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Project description:Arginine vasopressin (AVP) is a peptide hormone coded by the Avp gene, synthesized in the hypothalamus and secreted by the posterior pituitary. Dysregulation of AVP secretion contributes to a variety of human diseases. Previous studies of functional roles of AVP have been largely dependent on the use of Brattleboro rats, which manifest a spontaneous mutation in the Avp gene and lack circulating AVP. Despite their utility, Brattleboro rats are difficult to breed owing largely to the fixed nature of the Avp mutation, resulting in increased neonatal death and behavioral effects in the adults. Consequently, commercial breeders have ceased production, despite a continued need. Therefore, the main goal of this project is to create an effective experimental Avp knockout mouse model that could be used in renal and neuroendocrine research to study the control of water balance by AVP. We employed CRISPR/Cas9 to flox a portion of exon 2 of the Avp gene. Successful insertion of the two loxP sites was confirmed by PCR using primers flanking the targeted regions. Mice harboring the floxed allele were mated to B6.Cg-Tg(CAG-cre/Esr1*)5Amc/J mice that globally express a tamoxifen-inducible Cre recombinase. The resultant inducible Avp knockout mice (Cre+Avpflx/flx) show no signs of polydipsia or polyuria prior to induction, indicating that the floxed gene maintains its wild-type function. The administration of an exogenous inducer like tamoxifen to (8-10) week-old mice, induced Cre-mediated recombination that resulted in a decrease in urine osmolality from 2076 ± 138 to 122 ± 6 mOsm/kgH2O on day 31 after induction. Sanger sequencing demonstrated the expected 1245 bp deletion at the Avp locus. Immunoblotting of AQP2 in the inner medulla showed a significant decrease in AQP2 band density in (Cre+Avpflx/flx) mice to 27 ±1 4 % of values in Cre- floxed control mice. This inducible Avp knockout mouse model provides researchers with a valuable tool to investigate the consequences of Avp gene deletion in a controlled and inducible manner.

Project description:Stress is defined as a systemic nonspecific adaptive response to the stimulations from internal and external environment or psychological factors through coordinating series of complex systems, like nervous system, immune system and respiratory system. While it is well known that stress have profound negative effects on reproductive function, the mechanism of reproductive dysfunction is still far from perfect. Kisspeptin, which are known for regulating GnRH synthesis and secretion, affect the initiation of puberty and reproduction, have been shown to express glucocorticoid receptors(GR),and both acute and chronic stress significantly inhibit Kisspeptin expression. So, this study speculated that Kisspeptin might participate in the process of reproductive regulation during stress. However, when constructed stress models of GT1-7 cells(Derived from mouse hypothalamic neurons, could not only transcribe endogenous GnRH mRNA and release GnRH when depolarization, but also express Kisspeptin, G protein-coupled receptors) with DEX and tried to analyze the specific mechanism of stress inhibited Kisspeptin expression, opposite results(Dex improved Kisspeptin expression of GT1-7 cells) were obtained. Based on the neuroimmune system hypothesis of stress, this study speculated that the direct reason of stress inhibited Kisspeptin expression might be stress-induced inflammatory response rather than stress-elevated GC. Even so, the transcription of Il-1β decreased in BV-2 cells(Derived from mouse Microglia) after treated with DEX. Due to the proximity of Kisspeptin neurons and Microgila in arcuate nucleus(ARC) of hypothalamus, it is speculated that there maight be interaction between them. So, this study co-cultured GT1-7 cells and BV-2 cells, and found transcription of Kiss1 decreased and Il-1β increased. Decreased Kisspeptin expression due to inflammation of BV-2 cells and inflammation of BV-2 cells must due to changes of certain substances or molecules in GT1-7 cells after treated with DEX. To further explore the possible mechanism, this study used the highly sensitive miRNAs array to screen miRNAs which not only changed significantly in GT1-7 cells after treated with DEX but also associated with inflammation. Finally, 10 miRNAs obtained and further confirmed mmu-miR-146a-5P could inhibited the LPS-induced BV-2 cells inflammation, M1 polarization and apoptosis.

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Transcriptomic profiling reveals AVP-responsive molecular changes in GT1-7 GnRH neurons

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