title: A microRNA switch regulates the rise in hypothalamic GnRH production before puberty.
abstract: A sparse population of a few hundred primarily hypothalamic neurons forms the hub of a complex neuroglial network that controls reproduction in mammals by secreting the 'master molecule' gonadotropin-releasing hormone (GnRH). Timely postnatal changes in GnRH expression are essential for puberty and adult fertility. Here we report that a multilayered microRNA-operated switch with built-in feedback governs increased GnRH expression during the infantile-to-juvenile transition and that impairing microRNA synthesis in GnRH neurons leads to hypogonadotropic hypogonadism and infertility in mice. Two essential components of this switch, miR-200 and miR-155, respectively regulate Zeb1, a repressor of Gnrh transcriptional activators and Gnrh itself, and Cebpb, a nitric oxide-mediated repressor of Gnrh that acts both directly and through Zeb1, in GnRH neurons. This alteration in the delicate balance between inductive and repressive signals induces the normal GnRH-fuelled run-up to correct puberty initiation, and interfering with this process disrupts the neuroendocrine control of reproduction.
authors.affiliation: Inserm, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Jean-Pierre Aubert Research Centre, U1172, Lille, France.|University of Lille, FHU 1,000 Days for Health, School of Medicine, Lille, France.
authors.forename: Andrea
authors.initials: A
authors.lastname: Messina
authors.affiliation: Inserm, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Jean-Pierre Aubert Research Centre, U1172, Lille, France.|University of Lille, FHU 1,000 Days for Health, School of Medicine, Lille, France.|Columbia University Medical Center and Berrie Diabetes Center, New York, New York, USA.
authors.forename: Fanny
authors.initials: F
authors.lastname: Langlet
authors.affiliation: Inserm, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Jean-Pierre Aubert Research Centre, U1172, Lille, France.|University of Lille, FHU 1,000 Days for Health, School of Medicine, Lille, France.
authors.forename: Konstantina
authors.initials: K
authors.lastname: Chachlaki
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain.|Instituto Maimonides de Investigación Biomédica de Cordoba (IMIBIC/HURS), Cordoba, Spain.|CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Cordoba, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Roa
authors.affiliation: Inserm UMR1141 - PROTECT (Promoting Research Oriented Towards Early CNS Therapies), Paris, France.
authors.forename: Sowmyalakshmi
authors.initials: S
authors.lastname: Rasika
authors.affiliation: Inserm, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Jean-Pierre Aubert Research Centre, U1172, Lille, France.|University of Lille, FHU 1,000 Days for Health, School of Medicine, Lille, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Jouy
authors.affiliation: Inserm, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Jean-Pierre Aubert Research Centre, U1172, Lille, France.|University of Lille, FHU 1,000 Days for Health, School of Medicine, Lille, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gallet
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain.|Instituto Maimonides de Investigación Biomédica de Cordoba (IMIBIC/HURS), Cordoba, Spain.|CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Cordoba, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Gaytan
authors.affiliation: Inserm, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Jean-Pierre Aubert Research Centre, U1172, Lille, France.|University of Lille, FHU 1,000 Days for Health, School of Medicine, Lille, France.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Parkash
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain.|Instituto Maimonides de Investigación Biomédica de Cordoba (IMIBIC/HURS), Cordoba, Spain.|CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Cordoba, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Tena-Sempere
authors.affiliation: Inserm, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Jean-Pierre Aubert Research Centre, U1172, Lille, France.|University of Lille, FHU 1,000 Days for Health, School of Medicine, Lille, France.
authors.forename: Paolo
authors.initials: P
authors.lastname: Giacobini
authors.affiliation: Inserm, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Jean-Pierre Aubert Research Centre, U1172, Lille, France.|University of Lille, FHU 1,000 Days for Health, School of Medicine, Lille, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Prevot
mesh_terms: D000375:Aging; D000818:Animals; D005298:Fertility / Q000502:physiology; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism*; D007006:Hypogonadism / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D012098:Reproduction / Q000502:physiology*; D012741:Sexual Maturation / Q000502:physiology*
chemical_list: D035683:MicroRNAs; D007987:Gonadotropin-Releasing Hormone