Home News About Us Contact Contributors Disclaimer Privacy Policy Help FAQ

Home
Search
Quick Search
Advanced
Fulltext
Browse
Collections
Persons
My eDoc
Session History
Login
Name:
Password:
Documentation
Help
Support Wiki
Direct access to
document ID:


          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook 2016     Display Documents



ID: 724015.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook 2016
GnRH Neuron-Specific Ablation of Galphaq/11 Results in Only Partial Inactivation of the Neuroendocrine-Reproductive Axis in Both Male and Female Mice: In Vivo Evidence for Kiss1r-Coupled Galphaq/11-Independent GnRH Secretion
Authors:Babwah, A. V.; Navarro, V. M.; Ahow, M.; Pampillo, M.; Nash, C.; Fayazi, M.; Calder, M.; Elbert, A.; Urbanski, H. F.; Wettschureck, N.; Offermanns, S.; Carroll, R. S.; Bhattacharya, M.; Tobet, S. A.; Kaiser, U. B.
Date of Publication (YYYY-MM-DD):2015-09-16
Title of Journal:J Neurosci
Volume:35
Issue / Number:37
Start Page:12903
End Page:12916
Audience:Not Specified
Abstract / Description: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 Galphaq/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 beta-arrestin, and in mice lacking beta-arrestin-1 or -2, KP-triggered GnRH secretion is significantly diminished. Based on these findings, we hypothesized that ablation of Galphaq/11 in GnRH neurons would diminish but not completely block KP-triggered GnRH secretion and that Galphaq/11-independent GnRH secretion would be sufficient to maintain fertility. To test this, Gnaq (encodes Galphaq) was selectively inactivated in the GnRH neurons of global Gna11 (encodes Galpha11)-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 Galphaq/11-independent GnRH secretion and activation of the neuroendocrine-reproductive axis in Gnaq(d/d) mice. SIGNIFICANCE STATEMENT: 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 Galphaq/11-coupled receptor, we previously demonstrated that it could couple to and signal via non-Galphaq/11-coupled pathways. The present study confirms these findings and, more importantly, while it establishes Galphaq/11-coupled signaling as a major conduit of GnRH secretion, it also uncovers a significant role for non-Galphaq/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.
Free Keywords:Animals; Blastocyst/pathology; Embryonic Development; Female; GTP-Binding Protein alpha Subunits/*deficiency/physiology; Gene Expression Profiling; Genitalia, Female/pathology/physiopathology; Genitalia, Male/pathology/physiopathology; Gonadal Steroid Hormones/secretion; Gonadotropin-Releasing Hormone/antagonists & inhibitors/*physiology; Gonadotropins, Pituitary/pharmacology/secretion; Hypogonadism/genetics/pathology/*physiopathology; Hypothalamo-Hypophyseal System/physiopathology; Hypothalamus/pathology; Infertility, Female/embryology/genetics/*physiopathology; Infertility, Male/embryology/genetics/*physiopathology; Kisspeptins/pharmacology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons/secretion; Oligopeptides/pharmacology; Ovariectomy; Ovulation/drug effects; Peptide Fragments/pharmacology; Peptides/pharmacology; Phenotype; Receptors, G-Protein-Coupled; Spermatogenesis; GnRH; GnRH secretion; Gq; Kiss1r; kisspeptin; beta-arrestin
External Publication Status:published
Document Type:Article
Communicated by:n.n.
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115. 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. 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. Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523. The Children's Health Research Institute, Victoria Research Laboratories, London Ontario, N6C 2V5, Canada, Lawson Health Research Institute, London, Ontario N6A 4V2, Canada. 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. Department of Pharmacology, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany. Physiology and Pharmacology, and Oncology, University of Western Ontario, London, Ontario N6A 3K7, Canada.
Identifiers:ISSN:1529-2401 (Electronic) 0270-6474 (Linking) %R 10.1523/JNEUROSCI.0041-15.2015
URL:http://www.ncbi.nlm.nih.gov/pubmed/26377475
The scope and number of records on eDoc is subject to the collection policies defined by each institute - see "info" button in the collection browse view.