title: GnRH Neuron-Specific Ablation of Gαq/11 Results in Only Partial Inactivation of the Neuroendocrine-Reproductive Axis in Both Male and Female Mice: In Vivo Evidence for Kiss1r-Coupled Gαq/11-Independent GnRH Secretion.
abstract: The gonadotropin-releasing hormone (GnRH) is the master regulator of fertility and kisspeptin (KP) is a potent trigger of GnRH secretion from GnRH neurons. KP signals via KISS1R, a Gαq/11-coupled receptor, and mice bearing a global deletion of Kiss1r (Kiss1r(-/-)) or a GnRH neuron-specific deletion of Kiss1r (Kiss1r(d/d)) display hypogonadotropic hypogonadism and infertility. KISS1R also signals via β-arrestin, and in mice lacking β-arrestin-1 or -2, KP-triggered GnRH secretion is significantly diminished. Based on these findings, we hypothesized that ablation of Gαq/11 in GnRH neurons would diminish but not completely block KP-triggered GnRH secretion and that Gαq/11-independent GnRH secretion would be sufficient to maintain fertility. To test this, Gnaq (encodes Gαq) was selectively inactivated in the GnRH neurons of global Gna11 (encodes Gα11)-null mice by crossing Gnrh-Cre and Gnaq(fl/fl);Gna11(-/-) mice. Experimental Gnaq(fl/fl);Gna11(-/-);Gnrh-Cre (Gnaq(d/d)) and control Gnaq(fl/fl);Gna11(-/-) (Gnaq(fl/fl)) littermate mice were generated and subjected to reproductive profiling. This process revealed that testicular development and spermatogenesis, preputial separation, and anogenital distance in males and day of vaginal opening and of first estrus in females were significantly less affected in Gnaq(d/d) mice than in previously characterized Kiss1r(-/-) or Kiss1r(d/d) mice. Additionally, Gnaq(d/d) males were subfertile, and although Gnaq(d/d) females did not ovulate spontaneously, they responded efficiently to a single dose of gonadotropins. Finally, KP stimulation triggered a significant increase in gonadotropins and testosterone levels in Gnaq(d/d) mice. We therefore conclude that the milder reproductive phenotypes and maintained responsiveness to KP and gonadotropins reflect Gαq/11-independent GnRH secretion and activation of the neuroendocrine-reproductive axis in Gnaq(d/d) mice.
  
  
  CONCLUSIONS
  The gonadotropin-releasing hormone (GnRH) is the master regulator of fertility. Over the last decade, several studies have established that the KISS1 receptor, KISS1R, is a potent trigger of GnRH secretion and inactivation of KISS1R on the GnRH neuron results in infertility. While KISS1R is best understood as a Gαq/11-coupled receptor, we previously demonstrated that it could couple to and signal via non-Gαq/11-coupled pathways. The present study confirms these findings and, more importantly, while it establishes Gαq/11-coupled signaling as a major conduit of GnRH secretion, it also uncovers a significant role for non-Gαq/11-coupled signaling in potentiating reproductive development and function. This study further suggests that by augmenting signaling via these pathways, GnRH secretion can be enhanced to treat some forms of infertility.
authors.affiliation: The Children's Health Research Institute, Victoria Research Laboratories, London Ontario, N6C 2V5, Canada, Lawson Health Research Institute, London, Ontario N6A 4V2, Canada, Departments of Obstetrics and Gynaecology, Physiology and Pharmacology, and ababwah@uwo.ca.
authors.forename: Andy V
authors.initials: AV
authors.lastname: Babwah
authors.affiliation: Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Víctor M
authors.initials: VM
authors.lastname: Navarro
authors.affiliation: The Children's Health Research Institute, Victoria Research Laboratories, London Ontario, N6C 2V5, Canada, Lawson Health Research Institute, London, Ontario N6A 4V2, Canada, Physiology and Pharmacology, and.
authors.forename: Maryse
authors.initials: M
authors.lastname: Ahow
authors.affiliation: The Children's Health Research Institute, Victoria Research Laboratories, London Ontario, N6C 2V5, Canada, Lawson Health Research Institute, London, Ontario N6A 4V2, Canada, Departments of Obstetrics and Gynaecology.
authors.forename: Macarena
authors.initials: M
authors.lastname: Pampillo
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523.
authors.forename: Connor
authors.initials: C
authors.lastname: Nash
authors.affiliation: The Children's Health Research Institute, Victoria Research Laboratories, London Ontario, N6C 2V5, Canada, Lawson Health Research Institute, London, Ontario N6A 4V2, Canada, Physiology and Pharmacology, and.
authors.forename: Mehri
authors.initials: M
authors.lastname: Fayazi
authors.affiliation: The Children's Health Research Institute, Victoria Research Laboratories, London Ontario, N6C 2V5, Canada, Lawson Health Research Institute, London, Ontario N6A 4V2, Canada, Departments of Obstetrics and Gynaecology.
authors.forename: Michele
authors.initials: M
authors.lastname: Calder
authors.affiliation: The Children's Health Research Institute, Victoria Research Laboratories, London Ontario, N6C 2V5, Canada, Lawson Health Research Institute, London, Ontario N6A 4V2, Canada.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Elbert
authors.affiliation: Divisions of Neuroscience and Reproductive and Developmental Sciences, Oregon National Primate Research Center, Beaverton, Oregon 97006, Departments of Behavioral Neuroscience and Physiology and Pharmacology, Oregon Health & Sciences University, Portland, Oregon 97239, and.
authors.forename: Henryk F
authors.initials: HF
authors.lastname: Urbanski
authors.affiliation: Department of Pharmacology, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Wettschureck
authors.affiliation: Department of Pharmacology, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.affiliation: Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Rona S
authors.initials: RS
authors.lastname: Carroll
authors.affiliation: Physiology and Pharmacology, and Oncology, University of Western Ontario, London, Ontario N6A 3K7, Canada.
authors.forename: Moshmi
authors.initials: M
authors.lastname: Bhattacharya
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523.
authors.forename: Stuart A
authors.identifier: http://orcid.org/0000-0002-1615-7331
authors.initials: SA
authors.lastname: Tobet
authors.affiliation: Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Ursula B
authors.initials: UB
authors.lastname: Kaiser
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000473:pathology; D047108:Embryonic Development; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000172:deficiency* / Q000502:physiology; D020869:Gene Expression Profiling; D005836:Genitalia, Female / Q000473:pathology / Q000503:physiopathology; D005837:Genitalia, Male / Q000473:pathology / Q000503:physiopathology; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000502:physiology*; D006065:Gonadotropins, Pituitary / Q000378:metabolism / Q000494:pharmacology; D007006:Hypogonadism / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D007031:Hypothalamus / Q000473:pathology; D007247:Infertility, Female / Q000196:embryology / Q000235:genetics / Q000503:physiopathology*; D007248:Infertility, Male / Q000196:embryology / Q000235:genetics / Q000503:physiopathology*; D059648:Kisspeptins / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010052:Ovariectomy; D010060:Ovulation / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010641:Phenotype; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D013091:Spermatogenesis
chemical_list: C000603967:GP Antagonist-2A peptide; D044385:GTP-Binding Protein alpha Subunits; D012739:Gonadal Steroid Hormones; D006065:Gonadotropins, Pituitary; C491407:Kiss1 protein, mouse; C492248:Kiss1r protein, mouse; D059648:Kisspeptins; D009842:Oligopeptides; D010446:Peptide Fragments; D010455:Peptides; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; C000603966:metastin (68-121); D007987:Gonadotropin-Releasing Hormone; C057022:iturelix
keywords: GnRH; GnRH secretion; Gq; KISS1R; kisspeptin; β-arrestin