Crosstalk Between Glucocorticoid Receptor and Early-growth Response Protein 1 Accounts for Repression of Brain-derived Neurotrophic Factor Transcript 4 Expression. (10th February 2019)

• Record Type: Journal Article
• Authors: Chen, Hui; Amazit, Larbi; Lombès, Marc; Le Menuet, Damien
• Is Part Of: Neuroscience. Volume 399(2019)
• Page Start: 12
• Page End: 27
• Publication Date: 2019-02-10
• Subjects: BDNF brain-derived neurotrophic factor -- ChIP Chromatin Immunoprecipitation -- CRE cAMP response element -- CREB cAMP response element binding protein -- DEX dexamethasone -- EGR1 early growth response protein 1 -- EGR-RE early growth response protein response element -- FK forskolin -- GR glucocorticoid receptor -- IP immunoprecipitation -- N2A neuro-2a cell line -- PCN primary neuronal culture -- RU RU486 -- VEH vehicle; glucocorticoid receptor -- BDNF -- EGR1 -- promoter; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2018.12.012
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: GR represses BDNF expression in BZ neuron-like cells. Bdnf exon IV is sensitive to neuroexcitatory signals. GR represses exon IV binding on EGR1 response element. GR and EGR1 interact on Bdnf exon IV promoter. New crosstalk between GR, EGR1 and BDNF in neurons. Abstract: The brain-derived neurotrophic factor (BDNF) is a key player in brain functions such as synaptic plasticity, stress, and behavior. Its gene structure in rodents contains 8 untranslated exons (I to VIII) whose expression is finely regulated and which spliced onto a common and unique translated exon IX. Altered Bdnf expression is associated with many pathologies such as depression, Alzheimer's disease and addiction. Through binding to glucocorticoid receptor (GR), glucocorticoids play a pivotal role for stress responses, mood and neuronal plasticity. We recently showed in neuronal primary culture and in the immortalized neuronal-like BZ cells that GR repressed Bdnf expression, notably the bdnf exon IV containing mRNA isoform ( Bdnf4) via GR binding to a short 275-bp sequence of Bdnf promoter. Herein, we demonstrate by transient transfection experiments and mutagenesis in BZ cells that GR interacts with an early growth response protein 1 (EGR1) response element (EGR-RE) located in the transcription start site of Bdnf exon IV promoter. Using Chromatin Immunoprecipitation, we find that both GR and EGR1 bind to this promoter sequence in a glucocorticoid-dependent manner and demonstrate by co-immunoprecipitation that GR and EGR1 are interacting physically. Interestingly, EGR1 has been widely characterized as a regulator of brain plasticity. In conclusion, we deciphered a mechanism by which GR downregulates Bdnf expression, identifying a novel functional crosstalk between glucocorticoid pathways, immediate early growth response proteins and Bdnf . As all these factors are well-recognized germane for brain pathophysiology, these findings may have significant implications in neurosciences as well as in therapeutics.