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Cited by 138Nerve injury and regenerationEstrogen and related hormone effectsStress Responses and Cortisol

Glucocorticoid receptor represses brain-derived neurotrophic factor expression in neuron-like cells

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Chen, Hui, Lombès, Marc, Le Menuet, Damien·2017·Molecular Brain
DOI 10.1186/s13041-017-0295-xPMC PMC5389111
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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.

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  • Abnormal GR activation contributes to neuronal apoptosis and degeneration by reducing expression of BDNF and inhibiting cellular proliferation.

    “Abnormal GR activation contributes to neuronal apoptosis and degeneration by reducing the expression of BDNF and inhibiting cellular proliferation”

    From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Chen et al., 2017

    The Abstract reports that dexamethasone reduced BDNF mRNA in mouse neuronal cultures and that a GR antagonist abolished the effect. The Discussion suggests altered BDNF expression may affect neuronal structure and function, but the paper does not establish that GR activation causes neuronal apoptosis or degeneration, or that it inhibits cellular proliferation. (LLM, conf=0.88)

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  1. [2]Hohn A Leibrock J Bailey K Barde YA Identification and characterization of a novel member of the nerve growth factor/brain-derived neurotrophic factor family Nature 1990 344 6264 339 341 10.1038/344339a0 2314473 · DOI · Paper page
  2. [3]Kawamoto Y Nakamura S Nakano S Oka N Akiguchi I Kimura J Immunohistochemical localization of brain-derived neurotrophic factor in adult rat brain Neuroscience 1996 74 4 1209 1226 10.1016/0306-4522(96)00245-X 8895887 · DOI
  3. [4]Yan Q Rosenfeld RD Matheson CR Hawkins N Lopez OT Bennett L Welcher AA Expression of brain-derived neurotrophic factor protein in the adult rat central nervous system Neuroscience 1997 78 2 431 448 10.1016/S0306-4522(96)00613-6 9145800 · DOI
  4. [6]Bernd P The role of neurotrophins during early development Gene Expr 2008 14 4 241 250 10.3727/105221608786883799 19110723 PMC6042000 · DOI
  5. [7]Yamada K Mizuno M Nabeshima T Role for brain-derived neurotrophic factor in learning and memory Life Sci 2002 70 7 735 744 10.1016/S0024-3205(01)01461-8 11833737 · DOI
  6. [8]Tyler WJ Alonso M Bramham CR Pozzo-Miller LD From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning Learn Mem 2002 9 5 224 237 10.1101/lm.51202 12359832 PMC2806479 · DOI
  7. [9]Bolanos CA Nestler EJ Neurotrophic mechanisms in drug addiction Neuromolecular Med 2004 5 1 69 83 10.1385/NMM:5:1:069 15001814 · DOI
  8. [11]Bibel M Barde YA Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system Genes Dev 2000 14 23 2919 2937 10.1101/gad.841400 11114882 · DOI
  9. [12]Binder DK Scharfman HE Brain-derived neurotrophic factor Growth Factors 2004 22 3 123 131 10.1080/08977190410001723308 15518235 PMC2504526 · DOI
  10. [13]Castren E Neurotrophins as mediators of drug effects on mood, addiction, and neuroprotection Mol Neurobiol 2004 29 3 289 302 10.1385/MN:29:3:289 15181240 · DOI
  11. [14]Cattaneo E Zuccato C Tartari M Normal huntingtin function: an alternative approach to Huntington’s disease Nat Rev Neurosci 2005 6 12 919 930 10.1038/nrn1806 16288298 · DOI
  12. [15]Murer MG Yan Q Raisman-Vozari R Brain-derived neurotrophic factor in the control human brain, and in Alzheimer’s disease and Parkinson’s disease Prog Neurobiol 2001 63 1 71 124 10.1016/S0301-0082(00)00014-9 11040419 · DOI · Paper page
  13. [16]Russo-Neustadt AA Chen MJ Brain-derived neurotrophic factor and antidepressant activity Curr Pharm Des 2005 11 12 1495 1510 10.2174/1381612053764788 15892658 · DOI
  14. [17]Chao MV Neurotrophins and their receptors: a convergence point for many signalling pathways Nat Rev Neurosci 2003 4 4 299 309 10.1038/nrn1078 12671646 · DOI · Paper page
  15. [18]Aid T Kazantseva A Piirsoo M Palm K Timmusk T Mouse and rat BDNF gene structure and expression revisited J Neurosci Res 2007 85 3 525 535 10.1002/jnr.21139 17149751 PMC1878509 · DOI · Paper page
  16. [19]Baj G Leone E Chao MV Tongiorgi E Spatial segregation of BDNF transcripts enables BDNF to differentially shape distinct dendritic compartments Proc Natl Acad Sci U S A 2011 108 40 16813 16818 10.1073/pnas.1014168108 21933955 PMC3189043 · DOI
  17. [20]Palomer E Martin-Segura A Baliyan S Ahmed T Balschun D Venero C Martin MG Dotti CG Aging triggers a repressive chromatin state at bdnf promoters in hippocampal neurons Cell Rep 2016 16 11 2889 2900 10.1016/j.celrep.2016.08.028 27626660 · DOI
  18. [22]Nair A Vadodaria KC Banerjee SB Benekareddy M Dias BG Duman RS Vaidya VA Stressor-specific regulation of distinct brain-derived neurotrophic factor transcripts and cyclic AMP response element-binding protein expression in the postnatal and adult rat hippocampus Neuropsychopharmacology 2007 32 7 1504 1519 10.1038/sj.npp.1301276 17164818 · DOI · Paper page
  19. [23]Zhang Y Gu F Chen J Dong W Chronic antidepressant administration alleviates frontal and hippocampal BDNF deficits in CUMS rat Brain Res 2010 1366 141 148 10.1016/j.brainres.2010.09.095 20920483 · DOI
  20. [24]Nair B, Wong-Riley MT. Transcriptional Regulation of Brain-derived Neurotrophic Factor Coding Exon IX: Role of Nuclear Respiratory Factor 2. J Biol Chem. 2016;291(43):22583–593. PMC5077195 27624937
  21. [26]Joels M Krugers HJ Lucassen PJ Karst H Corticosteroid effects on cellular physiology of limbic cells Brain Res 2009 1293 91 100 10.1016/j.brainres.2009.03.036 19332034 · DOI
  22. [27]Le Menuet D Lombes M The neuronal mineralocorticoid receptor: from cell survival to neurogenesis Steroids 2014 91 11 19 10.1016/j.steroids.2014.05.018 24928721 · DOI
  23. [28]Lambert WM Xu CF Neubert TA Chao MV Garabedian MJ Jeanneteau FD Brain-derived neurotrophic factor signaling rewrites the glucocorticoid transcriptome via glucocorticoid receptor phosphorylation Mol Cell Biol 2013 33 18 3700 3714 10.1128/MCB.00150-13 23878391 PMC3753865 · DOI
  24. [29]Arango-Lievano M Lambert WM Bath KG Garabedian MJ Chao MV Jeanneteau F Neurotrophic-priming of glucocorticoid receptor signaling is essential for neuronal plasticity to stress and antidepressant treatment Proc Natl Acad Sci U S A 2015 112 51 15737 15742 26630005 PMC4697403
  25. [31]Duman RS Monteggia LM A neurotrophic model for stress-related mood disorders Biol Psychiatry 2006 59 12 1116 1127 10.1016/j.biopsych.2006.02.013 16631126 · DOI · Paper page
  26. [32]Li Y Luikart BW Birnbaum S Chen J Kwon CH Kernie SG Bassel-Duby R Parada LF TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment Neuron 2008 59 3 399 412 10.1016/j.neuron.2008.06.023 18701066 PMC2655199 · DOI · Paper page
  27. [33]Herman JP Cullinan WE Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis Trends Neurosci 1997 20 2 78 84 10.1016/S0166-2236(96)10069-2 9023876 · DOI · Paper page
  28. [34]Jankord R Herman JP Limbic regulation of hypothalamo-pituitary-adrenocortical function during acute and chronic stress Ann N Y Acad Sci 2008 1148 64 73 10.1196/annals.1410.012 19120092 PMC2637449 · DOI · Paper page
  29. [35]Murakami S Imbe H Morikawa Y Kubo C Senba E Chronic stress, as well as acute stress, reduces BDNF mRNA expression in the rat hippocampus but less robustly Neurosci Res 2005 53 2 129 139 10.1016/j.neures.2005.06.008 16024125 · DOI · Paper page
  30. [36]Dwivedi Y Rizavi HS Pandey GN Antidepressants reverse corticosterone-mediated decrease in brain-derived neurotrophic factor expression: differential regulation of specific exons by antidepressants and corticosterone Neuroscience 2006 139 3 1017 1029 10.1016/j.neuroscience.2005.12.058 16500030 PMC1513636 · DOI
  31. [37]Gourley SL Kedves AT Olausson P Taylor JR A history of corticosterone exposure regulates fear extinction and cortical NR2B, GluR2/3, and BDNF Neuropsychopharmacology 2009 34 3 707 716 10.1038/npp.2008.123 18719621 PMC3679657 · DOI · Paper page
  32. [38]Smith MA Makino S Kvetnansky R Post RM Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus J Neurosci 1995 15 3 Pt 1 1768 1777 7891134 PMC6578156
  33. [39]Asadi A Hedman E Widen C Zilliacus J Gustafsson JA Wikstrom AC FMS-like tyrosine kinase 3 interacts with the glucocorticoid receptor complex and affects glucocorticoid dependent signaling Biochem Biophys Res Commun 2008 368 3 569 574 10.1016/j.bbrc.2008.01.146 18261979 · DOI
  34. [40]Cheung LW Leung KW Wong CK Wong RN Wong AS Ginsenoside-Rg1 induces angiogenesis via non-genomic crosstalk of glucocorticoid receptor and fibroblast growth factor receptor-1 Cardiovasc Res 2011 89 2 419 425 10.1093/cvr/cvq300 20855522 · DOI
  35. [41]Kumamaru E Numakawa T Adachi N Kunugi H Glucocorticoid suppresses BDNF-stimulated MAPK/ERK pathway via inhibiting interaction of Shp2 with TrkB FEBS Lett 2011 585 20 3224 3228 10.1016/j.febslet.2011.09.010 21946312 · DOI
  36. [42]Kino T Jaffe H Amin ND Chakrabarti M Zheng YL Chrousos GP Pant HC Cyclin-dependent kinase 5 modulates the transcriptional activity of the mineralocorticoid receptor and regulates expression of brain-derived neurotrophic factor Mol Endocrinol 2010 24 5 941 952 10.1210/me.2009-0395 20357208 PMC2870940 · DOI
  37. [43]Ridder S Chourbaji S Hellweg R Urani A Zacher C Schmid W Zink M Hortnagl H Flor H Henn FA Mice with genetically altered glucocorticoid receptor expression show altered sensitivity for stress-induced depressive reactions J Neurosci 2005 25 26 6243 6250 10.1523/JNEUROSCI.0736-05.2005 15987954 PMC6725059 · DOI · Paper page
  38. [44]Daskalakis NP De Kloet ER Yehuda R Malaspina D Kranz TM Early Life Stress Effects on Glucocorticoid-BDNF Interplay in the Hippocampus Front Mol Neurosci 2015 8 68 10.3389/fnmol.2015.00068 26635521 PMC4644789 · DOI
  39. [46]Pruunsild P Sepp M Orav E Koppel I Timmusk T Identification of cis-elements and transcription factors regulating neuronal activity-dependent transcription of human BDNF gene J Neurosci 2011 31 9 3295 3308 10.1523/JNEUROSCI.4540-10.2011 21368041 PMC6623925 · DOI
  40. [47]Le Menuet D Zennaro MC Viengchareun S Lombes M Transgenic mouse models to study human mineralocorticoid receptor function in vivo Kidney Int 2000 57 4 1299 1306 10.1046/j.1523-1755.2000.00966.x 10760058 · DOI
  41. [48]Seibenhener ML, Wooten MW: Isolation and culture of hippocampal neurons from prenatal mice. J Vis Exp. 2012;(65). doi:10.3791/3634. PMC3476399 22871921 · DOI
  42. [49]Martinez Y Bena F Gimelli S Tirefort D Dubois-Dauphin M Krause KH Preynat-Seauve O Cellular diversity within embryonic stem cells: pluripotent clonal sublines show distinct differentiation potential J Cell Mol Med 2012 16 3 456 467 10.1111/j.1582-4934.2011.01334.x 21535399 PMC3822923 · DOI
  43. [50]Sarabdjitsingh RA Meijer OC de Kloet ER Specificity of glucocorticoid receptor primary antibodies for analysis of receptor localization patterns in cultured cells and rat hippocampus Brain Res 2010 1331 1 11 10.1016/j.brainres.2010.03.052 20307510 · DOI
  44. [51]Zuccotti A Kuhn S Johnson SL Franz C Singer W Hecker D Geisler HS Kopschall I Rohbock K Gutsche K Lack of brain-derived neurotrophic factor hampers inner hair cell synapse physiology, but protects against noise-induced hearing loss J Neurosci 2012 32 25 8545 8553 10.1523/JNEUROSCI.1247-12.2012 22723694 PMC6620992 · DOI
  45. [52]Le Billan F, Khan JA, Lamribet K, Viengchareun S, Bouligand J, Fagart J, Lombes M: Cistrome of the aldosterone-activated mineralocorticoid receptor in human renal cells. FASEB J. 2015. 26054365
  46. [53]Mifsud KR Reul JM Acute stress enhances heterodimerization and binding of corticosteroid receptors at glucocorticoid target genes in the hippocampus Proc Natl Acad Sci U S A 2016 113 40 11336 11341 10.1073/pnas.1605246113 27655894 PMC5056104 · DOI
  47. [54]Haffner MC Jurgeit A Berlato C Geley S Parajuli N Yoshimura A Doppler W Interaction and functional interference of glucocorticoid receptor and SOCS1 J Biol Chem 2008 283 32 22089 22096 10.1074/jbc.M801041200 18524780 · DOI
  48. [55]Salerno KM Jing X Diges CM Cornuet PK Glorioso JC Albers KM Sox11 modulates brain-derived neurotrophic factor expression in an exon promoter-specific manner J Neurosci Res 2012 90 5 1011 1019 10.1002/jnr.23010 22331573 PMC3296899 · DOI
  49. [56]Le Menuet D Viengchareun S Penfornis P Walker F Zennaro MC Lombes M Targeted oncogenesis reveals a distinct tissue-specific utilization of alternative promoters of the human mineralocorticoid receptor gene in transgenic mice J Biol Chem 2000 275 11 7878 7886 10.1074/jbc.275.11.7878 10713103 · DOI
  50. [57]Oakley RH Cidlowski JA The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease J Allergy Clin Immunol 2013 132 5 1033 1044 10.1016/j.jaci.2013.09.007 24084075 PMC4084612 · DOI · Paper page
  51. [58]Tuvikene J Pruunsild P Orav E Esvald EE Timmusk T AP-1 Transcription Factors Mediate BDNF-Positive Feedback Loop in Cortical Neurons J Neurosci 2016 36 4 1290 1305 10.1523/JNEUROSCI.3360-15.2016 26818516 PMC6604814 · DOI
  52. [59]Penfornis P Viengchareun S Le Menuet D Cluzeaud F Zennaro MC Lombes M The mineralocorticoid receptor mediates aldosterone-induced differentiation of T37i cells into brown adipocytes Am J Physiol Endocrinol Metab 2000 279 2 E386 394 10913039
  53. [60]Numakawa T Adachi N Richards M Chiba S Kunugi H Brain-derived neurotrophic factor and glucocorticoids: reciprocal influence on the central nervous system Neuroscience 2013 239 157 172 10.1016/j.neuroscience.2012.09.073 23069755 · DOI
  54. [61]Hellal-Levy C Couette B Fagart J Souque A Gomez-Sanchez C Rafestin-Oblin M Specific hydroxylations determine selective corticosteroid recognition by human glucocorticoid and mineralocorticoid receptors FEBS Lett 1999 464 1-2 9 13 10.1016/S0014-5793(99)01667-1 10611474 · DOI
  55. [62]Lombes M Kenouch S Souque A Farman N Rafestin-Oblin ME The mineralocorticoid receptor discriminates aldosterone from glucocorticoids independently of the 11 beta-hydroxysteroid dehydrogenase Endocrinology 1994 135 3 834 840 8070376
  56. [63]Dougherty EJ, Elinoff JM, Ferreyra GA, Hou A, Cai R, Sun J, Blaine KP, Wang S, Danner RL: Mineralocorticoid Receptor (MR) Trans-Activation of Inflammatory AP-1 Signaling: Dependence on DNA Sequence, MR Conformation, and AP-1 Family Member Expression. J Biol Chem 2016. PMC5095416 27650495
  57. [64]Hua G Paulen L Chambon P GR SUMOylation and formation of an SUMO-SMRT/NCoR1-HDAC3 repressing complex is mandatory for GC-induced IR nGRE-mediated transrepression Proc Natl Acad Sci U S A 2016 113 5 E626 634 10.1073/pnas.1522821113 26712002 PMC4747746 · DOI
  58. [66]Tao X Finkbeiner S Arnold DB Shaywitz AJ Greenberg ME Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism Neuron 1998 20 4 709 726 10.1016/S0896-6273(00)81010-7 9581763 · DOI · Paper page
  59. [67]Tao X West AE Chen WG Corfas G Greenberg ME A calcium-responsive transcription factor, CaRF, that regulates neuronal activity-dependent expression of BDNF Neuron 2002 33 3 383 395 10.1016/S0896-6273(01)00561-X 11832226 · DOI · Paper page
  60. [68]Jiang X Tian F Du Y Copeland NG Jenkins NA Tessarollo L Wu X Pan H Hu XZ Xu K BHLHB2 controls Bdnf promoter 4 activity and neuronal excitability J Neurosci 2008 28 5 1118 1130 10.1523/JNEUROSCI.2262-07.2008 18234890 PMC6671398 · DOI
  61. [69]Mallei A, Baj G, Ieraci A, Corna S, Musazzi L, Lee FS, Tongiorgi E, Popoli M: Expression and Dendritic Trafficking of BDNF-6 Splice Variant are Impaired in Knock-In Mice Carrying Human BDNF Val66Met Polymorphism. Int J Neuropsychopharmacol. 2015;18(12). PMC4675980 26108221

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Authors
Chen, H., Lombès, M., & Le Menuet, D.
Affiliations
Inserm (FR)
ORCID
Venue
Molecular Brain
Publisher
Springer Science and Business Media LLC
Published
2017-04-12
Volume
10
Issue
1
Pages
12-12
ISSN
1756-6606 (ISSN-L)
DOI
10.1186/s13041-017-0295-x
PMC
PMC5389111
OpenAlex
W2606919359
Cited by
138
References
8
Citations by year
2026: 23 · 2025: 16 · 2024: 15 · 2023: 8 · 2022: 16 · 2021: 14 · 2020: 13 · 2019: 16 · 2018: 13 · 2017: 4
FWCI
6.16
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Molecular Brain (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Agence Nationale de la Recherche (FR) (11-BSV1-028-01)
  • China Scholarship Council
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
glucocorticoid receptor, brain-derived neurotrophic factor, dexamethasone, RU486, transcriptional regulation
MeSH terms
Animals, Base Sequence, Cell Line, Dexamethasone, Exons, Glucocorticoids, Hippocampus, Neurons, Promoter Regions, Genetic, Protein Binding, Receptors, Glucocorticoid, Down-Regulation, Brain-Derived Neurotrophic Factor, Response Elements, Mice

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