title: Repressor element 1 silencing transcription factor (REST) controls radial migration and temporal neuronal specification during neocortical development.
abstract: Neurogenesis requires mechanisms that coordinate early cell-fate decisions, migration, and terminal differentiation. Here, we show that the transcriptional repressor, repressor element 1 silencing transcription factor (REST), regulates radial migration and the timing of neural progenitor differentiation during neocortical development, and that the regulation is contingent upon differential REST levels. Specifically, a sustained presence of REST blocks migration and greatly delays--but does not prevent--neuronal differentiation, resulting in a subcortical band heterotopia-like phenotype, reminiscent of loss of doublecortin. We further show that doublecortin is a direct gene target of REST, and that its overexpression rescues, at least in part, the aberrant phenotype caused by persistent presence of REST. Our studies support the view that the targeted down-regulation of REST to low levels in neural progenitors, and its subsequent disappearance during neurogenesis, is critical for timing the spatiotemporal transition of neural progenitor cells to neurons.
authors.affiliation: Department of Neurobiology and Behavior, and Howard Hughes Medical Institute, State University of New York, Stony Brook, NY 11794, USA. mandelg@ohsu.edu
authors.forename: Gail
authors.initials: G
authors.lastname: Mandel
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Fiondella
authors.forename: Matthew V
authors.initials: MV
authors.lastname: Covey
authors.forename: Diane D
authors.initials: DD
authors.lastname: Lu
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Loturco
authors.forename: Nurit
authors.initials: N
authors.lastname: Ballas
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D056970:Co-Repressor Proteins; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D000089622:Doublecortin Domain Proteins; D018274:Electroporation; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019579:Neocortex / Q000196:embryology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D056970:Co-Repressor Proteins; D017931:DNA Primers; D018076:DNA, Complementary; D000089622:Doublecortin Domain Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C121019:RCOR1 protein, human; D012097:Repressor Proteins