title: The master negative regulator REST/NRSF controls adult neurogenesis by restraining the neurogenic program in quiescent stem cells.
abstract: Transcriptional regulation is a critical mechanism in the birth, specification, and differentiation of granule neurons in the adult hippocampus. One of the first negative-acting transcriptional regulators implicated in vertebrate development is repressor element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF)--thought to regulate hundreds of neuron-specific genes--yet its function in the adult brain remains elusive. Here we report that REST/NRSF is required to maintain the adult neural stem cell (NSC) pool and orchestrate stage-specific differentiation. REST/NRSF recruits CoREST and mSin3A corepressors to stem cell chromatin for the regulation of pro-neuronal target genes to prevent precocious neuronal differentiation in cultured adult NSCs. Moreover, mice lacking REST/NRSF specifically in NSCs display a transient increase in adult neurogenesis that leads to a loss in the neurogenic capacity of NSCs and eventually diminished granule neurons. Our work identifies REST/NRSF as a master negative regulator of adult NSC differentiation and offers a potential molecular target for neuroregenerative approaches.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Zhengliang
authors.initials: Z
authors.lastname: Gao
authors.forename: Kerstin
authors.initials: K
authors.lastname: Ure
authors.forename: Peiguo
authors.initials: P
authors.lastname: Ding
authors.forename: Mostafa
authors.initials: M
authors.lastname: Nashaat
authors.forename: Laura
authors.initials: L
authors.lastname: Yuan
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hammer
authors.forename: Jenny
authors.initials: J
authors.lastname: Hsieh
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099229:RE1-Silencing Transcription Factor
chemical_list: D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor