The master negative regulator REST/NRSF controls adult neurogenesis by restraining the neurogenic program in quiescent stem cells

Zhengliang Gao, Kerstin Ure, Peiguo Ding, Mostafa Nashaat, Laura Yuan, Jing Ma, Robert E Hammer, Jenny Hsieh

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156 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)9772-9786
Number of pages15
JournalJournal of Neuroscience
Volume31
Issue number26
DOIs
StatePublished - Jun 29 2011

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ASJC Scopus subject areas

  • Neuroscience(all)

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