title: Defects During Mecp2 Null Embryonic Cortex Development Precede the Onset of Overt Neurological Symptoms.
abstract: MeCP2 is associated with several neurological disorders; of which, Rett syndrome undoubtedly represents the most frequent. Its molecular roles, however, are still unclear, and data from animal models often describe adult, symptomatic stages, while MeCP2 functions during embryonic development remain elusive. We describe the pattern and timing of Mecp2 expression in the embryonic neocortex highlighting its low but consistent expression in virtually all cells and show the unexpected occurrence of transcriptional defects in the Mecp2 null samples at a stage largely preceding the onset of overt symptoms. Through the deregulated expression of ionic channels and glutamatergic receptors, the lack of Mecp2 during early neuronal maturation leads to the reduction in the neuronal responsiveness to stimuli. We suggest that such features concur to morphological alterations that begin affecting Mecp2 null neurons around the perinatal age and become evident later in adulthood. We indicate MeCP2 as a key modulator of the transcriptional mechanisms regulating cerebral cortex development. Neurological phenotypes of MECP2 patients could thus be the cumulative result of different adverse events that are already present at stages when no obvious signs of the pathology are evident and are worsened by later impairments affecting the central nervous system during maturation and maintenance of its functionality.
authors.affiliation: San Raffaele Rett Research Unit, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bedogni
authors.affiliation: San Raffaele Rett Research Unit, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy.|Laboratory of Genetic and Epigenetic Control of Gene Expression, Division of Biomedical Research, Department of Theoretical and Applied Sciences, University of Insubria, Busto Arsizio, 21052 Varese, Italy.
authors.forename: Clementina
authors.initials: C
authors.lastname: Cobolli Gigli
authors.affiliation: Laboratory of Pharmacology and Brain Pathology, Humanitas Clinical and Research Center, Rozzano, 20089 Milan, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Pozzi
authors.affiliation: Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi", 20122 Milan, Italy.
authors.forename: Riccardo Lorenzo
authors.initials: RL
authors.lastname: Rossi
authors.affiliation: San Raffaele Rett Research Unit, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Linda
authors.initials: L
authors.lastname: Scaramuzza
authors.affiliation: Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi", 20122 Milan, Italy.
authors.forename: Grazisa
authors.initials: G
authors.lastname: Rossetti
authors.affiliation: Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi", 20122 Milan, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Pagani
authors.affiliation: Laboratory of Genetic and Epigenetic Control of Gene Expression, Division of Biomedical Research, Department of Theoretical and Applied Sciences, University of Insubria, Busto Arsizio, 21052 Varese, Italy.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kilstrup-Nielsen
authors.affiliation: Laboratory of Pharmacology and Brain Pathology, Humanitas Clinical and Research Center, Rozzano, 20089 Milan, Italy.|Dip di Biotecnologie Mediche e Medicina Traslazionale, Università di Milano, Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Matteoli
authors.affiliation: San Raffaele Rett Research Unit, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy.|Laboratory of Genetic and Epigenetic Control of Gene Expression, Division of Biomedical Research, Department of Theoretical and Applied Sciences, University of Insubria, Busto Arsizio, 21052 Varese, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Landsberger
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000196:embryology* / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D004558:Electric Stimulation; D005455:Fluorescent Antibody Technique; D018698:Glutamic Acid / Q000378:metabolism; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D015518:Rett Syndrome; D013997:Time Factors; D014158:Transcription, Genetic; D056969:Voltage-Sensitive Dye Imaging
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D018698:Glutamic Acid; D002118:Calcium
keywords: MeCP2 null cortex; embryonic cerebral cortex development; intrinsic neuronal excitability; neurological disorders; transcriptome