title: A regulatory loop between miR-132 and miR-125b involved in gonadotrope cells desensitization to GnRH.
abstract: The GnRH neurohormone is the main activator of the pituitary gonadotropins, LH and FSH. Here we investigated the contribution of microRNAs in mediating GnRH activation. We first established that miR-125b targets several actors of Gαq/11 signalling pathway, without altering Gαs pathway. We then showed that a Gαs-mediated, PKA-dependent phosphorylation of NSun2 methyltransferase leads to miR-125b methylation and thereby induces its down-regulation. We demonstrated that NSun2 mRNA is a target of miR-132 and that NSun2 may be inactivated by the PP1α phosphatase. Time-course analysis of GnRH treatment revealed an initial NSun2-dependent down-regulation of miR-125b with consecutive up-regulation of LH and FSH expression. Increase of miR-132 and of the catalytic subunit of PP1α then contributed to NSun2 inactivation and to the return of miR-125b to its steady-state level. The Gαq/11-dependent pathway was thus again silenced, provoking the down-regulation of LH, FSH and miR-132. Overall, this study reveals that a regulatory loop that tends to maintain or restore high and low levels of miR-125b and miR-132, respectively, is responsible for gonadotrope cells desensitization to sustained GnRH. A dysregulation of this loop might be responsible for the inverted dynamics of these two miRNAs reported in several neuronal and non-neuronal pathologies.
authors.affiliation: Université Paris-Diderot, Sorbonne Paris Cité, Biologie Fonctionnelle et Adaptative (BFA), F-75013 Paris, France.|Centre National pour la Recherche Scientifique (CNRS) UMR 8251, Paris, France.|Physiologie de l'axe gonadotrope, Institut National de la Santé et de la Recherche Médicale (INSERM) U1133 Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Lannes
authors.affiliation: Université Paris-Diderot, Sorbonne Paris Cité, Biologie Fonctionnelle et Adaptative (BFA), F-75013 Paris, France.|Centre National pour la Recherche Scientifique (CNRS) UMR 8251, Paris, France.|Physiologie de l'axe gonadotrope, Institut National de la Santé et de la Recherche Médicale (INSERM) U1133 Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: L'hôte
authors.affiliation: Université Paris-Diderot, Sorbonne Paris Cité, Biologie Fonctionnelle et Adaptative (BFA), F-75013 Paris, France.|Centre National pour la Recherche Scientifique (CNRS) UMR 8251, Paris, France.|Physiologie de l'axe gonadotrope, Institut National de la Santé et de la Recherche Médicale (INSERM) U1133 Paris, France.
authors.forename: Ambra
authors.initials: A
authors.lastname: Fernandez-Vega
authors.affiliation: Université Paris-Diderot, Sorbonne Paris Cité, Biologie Fonctionnelle et Adaptative (BFA), F-75013 Paris, France.|Centre National pour la Recherche Scientifique (CNRS) UMR 8251, Paris, France.|Physiologie de l'axe gonadotrope, Institut National de la Santé et de la Recherche Médicale (INSERM) U1133 Paris, France.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Garrel
authors.affiliation: Université Paris-Diderot, Sorbonne Paris Cité, Biologie Fonctionnelle et Adaptative (BFA), F-75013 Paris, France.|Centre National pour la Recherche Scientifique (CNRS) UMR 8251, Paris, France.|Physiologie de l'axe gonadotrope, Institut National de la Santé et de la Recherche Médicale (INSERM) U1133 Paris, France.
authors.forename: Jean-Noël
authors.initials: JN
authors.lastname: Laverrière
authors.affiliation: Université Paris-Diderot, Sorbonne Paris Cité, Biologie Fonctionnelle et Adaptative (BFA), F-75013 Paris, France.|Centre National pour la Recherche Scientifique (CNRS) UMR 8251, Paris, France.|Physiologie de l'axe gonadotrope, Institut National de la Santé et de la Recherche Médicale (INSERM) U1133 Paris, France.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Cohen-Tannoudji
authors.affiliation: Université Paris-Diderot, Sorbonne Paris Cité, Biologie Fonctionnelle et Adaptative (BFA), F-75013 Paris, France.|Centre National pour la Recherche Scientifique (CNRS) UMR 8251, Paris, France.|Physiologie de l'axe gonadotrope, Institut National de la Santé et de la Recherche Médicale (INSERM) U1133 Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Quérat
mesh_terms: D000818:Animals; D002460:Cell Line; D052681:Gonadotrophs / Q000378:metabolism* / Q000473:pathology; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction
chemical_list: C546976:MIRN132 microRNA, mouse; C548821:MIRN132 microRNA, rat; D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; D007987:Gonadotropin-Releasing Hormone