title: Differential Expression and Regulation of Brain-Derived Neurotrophic Factor (BDNF) mRNA Isoforms in Brain Cells from Mecp2(308/y) Mouse Model.
abstract: Rett syndrome (RTT) is a severe neurodevelopmental disease caused by mutations in methyl-CpG-binding protein 2 (MECP2), which encodes a transcriptional modulator of many genes including BDNF. BDNF comprises nine distinct promoter regions, each triggering the expression of a specific transcript. The role of this diversity of transcripts remains unknown. MeCP2 being highly expressed in neurons, RTT was initially considered as a neuronal disease. However, recent studies have shown that MeCP2 was also expressed in astrocytes. Though several studies explored Bdnf IV expression in Mecp2-deficient mice, the differential expression of Bdnf isoforms in Mecp2-deficient neurons and astrocytes was never studied. By using TaqMan technology and a mouse model expressing a truncated Mecp2 (Mecp2(308/y)), we firstly showed in neurons that Bdnf transcripts containing exon I, IIb, IIc, IV, and VI are prominently expressed, whereas in astrocytes, Bdnf transcript containing exon VI is preferentially expressed, suggesting a specific regulation of Bdnf expression at the cellular level. Secondly, we confirmed the repressive role of Mecp2 only on the expression of Bdnf VI in neurons. Our data suggested that the truncated Mecp2 protein maintains its function on Bdnf expression regulation in neurons and in astrocytes. Interestingly, we observed that Bdnf transcripts (I and IXA), regulated by neural activity induced by bicuculline in Mecp2(308/y) neurons, were not affected by histone deacetylase inhibition. In contrast, Bdnf transcripts (IIb, IIc, and VI), regulated by histone deacetylation, were not affected by bicuculline treatment in wild-type and Mecp2(308/y) neurons. All these results reflect the complexity of regulation of Bdnf gene.
authors: Institut Cochin, INSERM U1016, Génétique, Physiopathologie et Approches Pharmacologiques des Maladies Neurodéveloppementales, Université Paris Descartes, Paris, France.
authors: Audrey
authors: A
authors: Rousseaud
authors: Institut Cochin, INSERM U1016, Génétique, Physiopathologie et Approches Pharmacologiques des Maladies Neurodéveloppementales, Université Paris Descartes, Paris, France.
authors: Chloé
authors: C
authors: Delépine
authors: Institut Cochin, INSERM U1016, Génétique, Physiopathologie et Approches Pharmacologiques des Maladies Neurodéveloppementales, Université Paris Descartes, Paris, France.|Laboratoire de Biochimie et Génétique Moléculaire, Assistance Publique - Hôpitaux de Paris, GHU Cochin-Broca-Hôtel Dieu, Paris, France.
authors: Juliette
authors: J
authors: Nectoux
authors: Institut Cochin, INSERM U1016, Génétique, Physiopathologie et Approches Pharmacologiques des Maladies Neurodéveloppementales, Université Paris Descartes, Paris, France.
authors: Pierre
authors: P
authors: Billuart
authors: Institut Cochin, INSERM U1016, Génétique, Physiopathologie et Approches Pharmacologiques des Maladies Neurodéveloppementales, Université Paris Descartes, Paris, France. thierry.bienvenu@inserm.fr.|Laboratoire de Biochimie et Génétique Moléculaire, Assistance Publique - Hôpitaux de Paris, GHU Cochin-Broca-Hôtel Dieu, Paris, France. thierry.bienvenu@inserm.fr.
authors: Thierry
authors: T
authors: Bienvenu
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005091:Exons; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D020033:Protein Isoforms; D012333:RNA, Messenger
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