Kisspeptin–GPR54 Signaling Is Essential for Preovulatory Gonadotropin-Releasing Hormone Neuron Activation and the Luteinizing Hormone Surge

TLDR

Kisspeptin and its receptor GPR54 are central to fertility regulation, with GnRH neurons thought to be the primary site of this signaling. The study aimed to determine whether kisspeptin–GPR54 signaling is required for GnRH neuron activation and the LH surge that triggers ovulation. Using mouse models, the authors performed dual‑label immunocytochemistry, steroid‑replacement protocols, and examined Gpr54‑ and Kiss1‑null mice to assess GnRH neuron activity and LH secretion. Results showed that kisspeptin–GPR54 signaling is essential for GnRH neuron activation and LH surge, as mutants lacked both c‑FOS‑positive GnRH neurons and LH surges, highlighting therapeutic potential for fertility regulation.

Abstract

Kisspeptin and its receptor GPR54 have recently been identified as key signaling partners in the neural control of fertility in animal models and humans. The gonadotropin-releasing hormone (GnRH) neurons represent the final output neurons of the neural network controlling fertility and are suspected to be the primary locus of kisspeptin–GPR54 signaling. Using mouse models, the present study addressed whether kisspeptin and GPR54 have a key role in the activation of GnRH neurons to generate the luteinizing hormone (LH) surge responsible for ovulation. Dual-label immunocytochemistry experiments showed that 40–60% of kisspeptin neurons in the rostral periventricular area of the third ventricle (RP3V) expressed estrogen receptor α and progesterone receptors. Using an ovariectomized, gonadal steroid-replacement regimen, which reliably generates an LH surge, ∼30% of RP3V kisspeptin neurons were found to express c-FOS in surging mice compared with 0% in nonsurging controls. A strong correlation was found between the percentage of c-FOS-positive kisspeptin neurons and the percentage of c-FOS-positive GnRH neurons. To evaluate whether kisspeptin and/or GPR54 were essential for GnRH neuron activation and the LH surge, Gpr54 - and Kiss1 -null mice were examined. Whereas wild-type littermates all exhibited LH surges and c-FOS in ∼50% of their GnRH neurons, none of the mutant mice from either line showed an LH surge or any GnRH neurons with c-FOS. These observations provide the first evidence that kisspeptin–GPR54 signaling is essential for GnRH neuron activation that initiates ovulation. This broadens considerably the potential roles and therapeutic possibilities for kisspeptin and GPR54 in fertility regulation.