title: Kisspeptin-gpr54 signaling at the GnRH neuron is necessary for negative feedback regulation of luteinizing hormone secretion in female mice.
abstract: Kisspeptin-Gpr54 signaling is critical for regulating the activity of gonadotropin-releasing hormone (GnRH) neurons in mammals. Previous studies have shown that the negative feedback mechanism is disrupted in global Gpr54-null mutants. The present investigation aimed to determine (1) if a lack of cyclical estrogen exposure of the GnRH neuronal network in the life-long hypogonadotropic Gpr54-null mice contributed to their failed negative feedback mechanism and (2) the cellular location of disrupted kisspeptin-Gpr54 signaling. Plasma luteinizing hormone (LH) concentrations were determined in individual adult female mice when intact, following ovariectomy (OVX) and in response to an acute injection of 17β-estradiol (E2). Control mice exhibited a characteristic rise in LH after OVX that was suppressed by acute E2. Global Gpr54-null mice failed to exhibit any post-OVX increase in LH or response to E2. Adult female global Gpr54-null mice given a cyclical regimen of estradiol for three cycles prior to OVX also failed to exhibit any post-OVX increase in LH or response to E2. To address whether Gpr54 signaling at the GnRH neuron itself was necessary for the failed response to OVX in global Gpr54-null animals, adult female mice with a GnRH neuron-selective deletion of Gpr54 were examined. These mice also failed to exhibit any post-OVX increase in LH or response to E2. These experiments demonstrate defective negative feedback in global Gpr54-null mice that cannot be attributed to a lack of prior exposure of the GnRH neuronal network to cyclical estradiol. The absence of negative feedback in GnRH neuron-selective Gpr54-null mice demonstrates the necessity of direct kisspeptin signaling at the GnRH neuron for this mechanism to occur.
authors.affiliation: Centre for Neuroendocrinology, Department of Physiology, School of Medical Sciences, University of Otago, Dunedin, New Zealand.
authors.forename: Shel-Hwa
authors.initials: SH
authors.lastname: Yeo
authors.forename: Jenny
authors.initials: J
authors.lastname: Clarkson
authors.forename: Allan E
authors.initials: AE
authors.lastname: Herbison
mesh_terms: D000818:Animals; D001774:Blood Chemical Analysis; D004958:Estradiol / Q000008:administration & dosage; D004967:Estrogens / Q000008:administration & dosage / Q000378:metabolism; D025461:Feedback, Physiological / Q000187:drug effects; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D059648:Kisspeptins / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000097:blood / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010052:Ovariectomy; D010507:Periodicity; D010902:Pituitary Gland / Q000187:drug effects / Q000502:physiology; D011863:Radioimmunoassay; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D000074502:Receptors, Kisspeptin-1
chemical_list: D004967:Estrogens; C492248:Kiss1r protein, mouse; D059648:Kisspeptins; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D007987:Gonadotropin-Releasing Hormone; D004958:Estradiol; D007986:Luteinizing Hormone