title: Glucocorticoid receptor represses brain-derived neurotrophic factor expression in neuron-like cells.
abstract: Brain-derived neurotrophic factor (BDNF) is involved in many functions such as neuronal growth, survival, synaptic plasticity and memorization. Altered expression levels are associated with many pathological situations such as depression, epilepsy, Alzheimer's, Huntington's and Parkinson's diseases. Glucocorticoid receptor (GR) is also crucial for neuron functions, via binding of glucocorticoid hormones (GCs). GR actions largely overlap those of BDNF. It has been proposed that GR could be a regulator of BDNF expression, however the molecular mechanisms involved have not been clearly defined yet. Herein, we analyzed the effect of a GC agonist dexamethasone (DEX) on BDNF expression in mouse neuronal primary cultures and in the newly characterized, mouse hippocampal BZ cell line established by targeted oncogenesis. Mouse Bdnf gene exhibits a complex genomic structure with 8 untranslated exons (I to VIII) splicing onto one common and unique coding exon IX. We found that DEX significantly downregulated total BDNF mRNA expression by around 30%. Expression of the highly expressed exon IV and VI containing transcripts was also reduced by DEX. The GR antagonist RU486 abolished this effect, which is consistent with specific GR-mediated action. Transient transfection assays allowed us to define a short 275 bp region within exon IV promoter responsible for GR-mediated Bdnf repression. Chromatin immunoprecipitation experiments demonstrated GR recruitment onto this fragment, through unidentified transcription factor tethering. Altogether, GR downregulates Bdnf expression through direct binding to Bdnf regulatory sequences. These findings bring new insights into the crosstalk between GR and BDNF signaling pathways both playing a major role in physiology and pathology of the central nervous system.
authors.affiliation: Inserm 1185, Fac Med Paris Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Inserm 1185, Fac Med Paris Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France.|Service d'Endocrinologie et des Maladies de la Reproduction, Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Le Kremlin Bicêtre, F-94275, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Lombès
authors.affiliation: Inserm 1185, Fac Med Paris Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France. damien.le-menuet@u-psud.fr.
authors.forename: Damien
authors.identifier: 0000-0002-0802-7190
authors.initials: D
authors.lastname: Le Menuet
mesh_terms: D000818:Animals; D001483:Base Sequence; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D005091:Exons / Q000235:genetics; D005938:Glucocorticoids / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone
keywords: Brain-derived neurotrophic factor; Glucocorticoid receptor; Glucocorticoids; Promoters