title: Astrocyte Transcriptome from the Mecp2(308)-Truncated Mouse Model of Rett Syndrome.
abstract: Mutations in the gene encoding the transcriptional modulator methyl-CpG binding protein 2 (MeCP2) are responsible for the neurodevelopmental disorder Rett syndrome which is one of the most frequent sources of intellectual disability in women. Recent studies showed that loss of Mecp2 in astrocytes contributes to Rett-like symptoms and restoration of Mecp2 can rescue some of these defects. The goal of this work is to compare gene expression profiles of wild-type and mutant astrocytes from Mecp2(308/y) mice (B6.129S-MeCP2<tm1Heto>/J) by using Affymetrix mouse 2.0 microarrays. Results were confirmed by quantitative real-time RT-PCR and by Western blot analysis. Gene set enrichment analysis utilizing Ingenuity Pathways was employed to identify pathways disrupted by Mecp2 deficiency. A total of 2152 genes were statistically differentially expressed between wild-type and mutated samples, including 1784 coding transcripts. However, only 257 showed fold changes >1.2. We confirmed our data by replicative studies in independent primary cultures of cortical astrocytes from Mecp2-deficient mice. Interestingly, two genes known to encode secreted proteins, chromogranin B and lipocalin-2, showed significant dysregulation. These proteins secreted from Mecp2-deficient glia may exert negative non-cell autonomous effects on neuronal properties, including dendritic morphology. Moreover, transcriptional profiling revealed altered Nr2f2 expression which may explain down- and upregulation of several target genes in astrocytes such as Ccl2, Lcn2 and Chgb. Unraveling Nr2f2 involvement in Mecp2-deficient astrocytes could pave the way for a better understanding of Rett syndrome pathophysiology and offers new therapeutic perspectives.
authors.affiliation: Inserm, U1016, Faculté de Médecine, Laboratoire de Génétique et de Physiopathologie des Maladies Mentales, Institut Cochin, 24 Rue du Faubourg Saint Jacques, 75014, Paris, France.|Cnrs, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Chloé
authors.initials: C
authors.lastname: Delépine
authors.affiliation: Inserm, U1016, Faculté de Médecine, Laboratoire de Génétique et de Physiopathologie des Maladies Mentales, Institut Cochin, 24 Rue du Faubourg Saint Jacques, 75014, Paris, France.|Cnrs, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Groupe Universitaire Paris Centre, Site Cochin, Laboratoire de Biochimie et Génétique Moléculaire, Assistance Publique - Hôpitaux de Paris, 27 rue du Faubourg Saint Jacques, 75014, Paris, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Nectoux
authors.affiliation: Inserm, U1016, Faculté de Médecine, Laboratoire de Génétique et de Physiopathologie des Maladies Mentales, Institut Cochin, 24 Rue du Faubourg Saint Jacques, 75014, Paris, France.|Cnrs, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Letourneur
authors.affiliation: Inserm, U1016, Faculté de Médecine, Laboratoire de Génétique et de Physiopathologie des Maladies Mentales, Institut Cochin, 24 Rue du Faubourg Saint Jacques, 75014, Paris, France.|Cnrs, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Baud
authors.affiliation: Inserm, U1016, Faculté de Médecine, Laboratoire de Génétique et de Physiopathologie des Maladies Mentales, Institut Cochin, 24 Rue du Faubourg Saint Jacques, 75014, Paris, France.|Cnrs, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.affiliation: Inserm, U1016, Faculté de Médecine, Laboratoire de Génétique et de Physiopathologie des Maladies Mentales, Institut Cochin, 24 Rue du Faubourg Saint Jacques, 75014, Paris, France.|Cnrs, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Billuart
authors.affiliation: Inserm, U1016, Faculté de Médecine, Laboratoire de Génétique et de Physiopathologie des Maladies Mentales, Institut Cochin, 24 Rue du Faubourg Saint Jacques, 75014, Paris, France. thierry.bienvenu@inserm.fr.|Cnrs, UMR8104, Paris, France. thierry.bienvenu@inserm.fr.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France. thierry.bienvenu@inserm.fr.|Groupe Universitaire Paris Centre, Site Cochin, Laboratoire de Biochimie et Génétique Moléculaire, Assistance Publique - Hôpitaux de Paris, 27 rue du Faubourg Saint Jacques, 75014, Paris, France. thierry.bienvenu@inserm.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Bienvenu
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D051837:COUP Transcription Factor II / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology; D053378:Chromogranin B / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D000071068:Lipocalin-2; D054834:Lipocalins / Q000378:metabolism; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D016328:NF-kappa B / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000378:metabolism; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D015518:Rett Syndrome / Q000235:genetics* / Q000473:pathology; D059467:Transcriptome
chemical_list: D000209:Acute-Phase Proteins; D051837:COUP Transcription Factor II; D053378:Chromogranin B; D000071068:Lipocalin-2; D054834:Lipocalins; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; C497587:Nr2f2 protein, mouse; D015513:Oncogene Proteins; C506137:chromogranin B, mouse; C071332:Lcn2 protein, mouse
keywords: Astrocyte; Mecp2; NF-κB pathway; Nr2f2; Rett syndrome; Transcriptome