title: Repressor element 1 silencing transcription factor couples loss of pluripotency with neural induction and neural differentiation.
abstract: Neural differentiation of embryonic stem cells (ESCs) requires coordinated repression of the pluripotency regulatory program and reciprocal activation of the neurogenic regulatory program. Upon neural induction, ESCs rapidly repress expression of pluripotency genes followed by staged activation of neural progenitor and differentiated neuronal and glial genes. The transcriptional factors that underlie maintenance of pluripotency are partially characterized whereas those underlying neural induction are much less explored, and the factors that coordinate these two developmental programs are completely unknown. One transcription factor, REST (repressor element 1 silencing transcription factor), has been linked with terminal differentiation of neural progenitors and more recently, and controversially, with control of pluripotency. Here, we show that in the absence of REST, coordination of pluripotency and neural induction is lost and there is a resultant delay in repression of pluripotency genes and a precocious activation of both neural progenitor and differentiated neuronal and glial genes. Furthermore, we show that REST is not required for production of radial glia-like progenitors but is required for their subsequent maintenance and differentiation into neurons, oligodendrocytes, and astrocytes. We propose that REST acts as a regulatory hub that coordinates timely repression of pluripotency with neural induction and neural differentiation.
authors.affiliation: Centre for the Cellular Basis of Behaviour, Department of Neuroscience, The James Black Centre, King's College London, Institute of Psychiatry, London, UK.
authors.forename: Chiara
authors.initials: C
authors.lastname: Soldati
authors.forename: Angela
authors.initials: A
authors.lastname: Bithell
authors.forename: Caroline
authors.initials: C
authors.lastname: Johnston
authors.forename: Kee-Yew
authors.initials: KY
authors.lastname: Wong
authors.forename: Siaw-Wei
authors.initials: SW
authors.lastname: Teng
authors.forename: Vassilios
authors.initials: V
authors.lastname: Beglopoulos
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Stanton
authors.forename: Noel J
authors.initials: NJ
authors.lastname: Buckley
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002454:Cell Differentiation; D004149:Dioxoles / Q000494:pharmacology; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D051379:Mice; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000378:metabolism / Q000502:physiology*; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000099229:RE1-Silencing Transcription Factor
chemical_list: D001549:Benzamides; D004149:Dioxoles; D018125:Receptors, Transforming Growth Factor beta; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide