title: Direct Actions of Kisspeptins on GnRH Neurons Permit Attainment of Fertility but are Insufficient to Fully Preserve Gonadotropic Axis Activity.
abstract: Kisspeptins, ligands of the receptor, Gpr54, are potent stimulators of puberty and fertility. Yet, whether direct kisspeptin actions on GnRH neurons are sufficient for the whole repertoire of their reproductive effects remains debatable. To dissect out direct vs. indirect effects of kisspeptins on GnRH neurons in vivo, we report herein the detailed reproductive/gonadotropic characterization of a Gpr54 null mouse line with selective re-introduction of Gpr54 expression only in GnRH cells (Gpr54(-/-)Tg; rescued). Despite preserved fertility, adult rescued mice displayed abnormalities in gonadal microstructure, with signs of precocious ageing in females and elevated LH levels with normal-to-low testosterone secretion in males. Gpr54(-/-)Tg rescued mice showed also altered gonadotropin responses to negative feedback withdrawal, while luteinizing hormone responses to various gonadotropic regulators were variably affected, with partially blunted relative (but not absolute) responses to kisspeptin-10, NMDA and the agonist of tachykinin receptors, NK2R. Our data confirm that direct effects of kisspeptins on GnRH cells are sufficient to attain fertility. Yet, such direct actions appear to be insufficient to completely preserve proper functionality of gonadotropic axis, suggesting a role of kisspeptin signaling outside GnRH cells.
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Córdoba; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III; Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofia (IMIBIC/HURS), 14004 Córdoba, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: León
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Córdoba; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III; Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofia (IMIBIC/HURS), 14004 Córdoba, Spain.
authors.forename: Alexia
authors.initials: A
authors.lastname: Barroso
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Córdoba; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III; Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofia (IMIBIC/HURS), 14004 Córdoba, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Vázquez
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Córdoba; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III; Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofia (IMIBIC/HURS), 14004 Córdoba, Spain.
authors.forename: David
authors.initials: D
authors.lastname: García-Galiano
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Córdoba; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III; Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofia (IMIBIC/HURS), 14004 Córdoba, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Manfredi-Lozano
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Córdoba; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III; Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofia (IMIBIC/HURS), 14004 Córdoba, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Ruiz-Pino
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Córdoba; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III; Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofia (IMIBIC/HURS), 14004 Córdoba, Spain.
authors.forename: Violeta
authors.initials: V
authors.lastname: Heras
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Córdoba; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III; Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofia (IMIBIC/HURS), 14004 Córdoba, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Romero-Ruiz
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Córdoba; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III; Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofia (IMIBIC/HURS), 14004 Córdoba, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Roa
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Córdoba; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III; Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofia (IMIBIC/HURS), 14004 Córdoba, Spain.|Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Günther
authors.initials: G
authors.lastname: Schutz
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Córdoba; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III; Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofia (IMIBIC/HURS), 14004 Córdoba, Spain.|Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Milen
authors.initials: M
authors.lastname: Kirilov
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Córdoba; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III; Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofia (IMIBIC/HURS), 14004 Córdoba, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Gaytan
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Córdoba; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III; Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofia (IMIBIC/HURS), 14004 Córdoba, Spain.
authors.forename: Leonor
authors.initials: L
authors.lastname: Pinilla
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Córdoba; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III; Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofia (IMIBIC/HURS), 14004 Córdoba, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Tena-Sempere
mesh_terms: D000818:Animals; D025461:Feedback, Physiological; D005260:Female; D005298:Fertility / Q000187:drug effects*; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D006062:Gonadotropins / Q000378:metabolism; D059648:Kisspeptins / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D010053:Ovary / Q000378:metabolism / Q000648:ultrastructure; D010641:Phenotype; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D000074502:Receptors, Kisspeptin-1; D012098:Reproduction; D013737:Testis / Q000378:metabolism
chemical_list: D006062:Gonadotropins; C492248:Kiss1r protein, mouse; D059648:Kisspeptins; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D007987:Gonadotropin-Releasing Hormone