The master negative regulator REST/NRSF controls adult neurogenesis by restraining the neurogenic program in quiescent stem cells.
The master negative regulator REST/NRSF controls adult neurogenesis by restraining the neurogenic program in quiescent stem cells.
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DOI：
10.1523/jneurosci.1604-11.2011
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发表时间：
2011-06-29
期刊：
影响因子：
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通讯作者：
Hsieh J
中科院分区：
文献类型：
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作者：
Gao Z;Ure K;Ding P;Nashaat M;Yuan L;Ma J;Hammer RE;Hsieh J
转录调控是成年海马区颗粒神经元产生、特化和分化的关键机制。与脊椎动物发育有关的第一个负作用转录调控因子之一是REST/NRSF-被认为调节数百个神经元特定基因-然而它在成年大脑中的功能仍然难以捉摸。在这里，我们报告REST/NRSF是维持成体神经干细胞库和协调阶段特异性分化所必需的。REST/NRSF招募Corest和mSin3A辅阻遏子到干细胞染色质，以调节前神经元靶基因，以防止培养的成年神经干细胞的早熟神经元分化。此外，缺乏针对NSCs的REST/NRSF的小鼠表现出成年神经发生的一过性增加，导致NSCs的神经发生能力丧失，并最终减少颗粒神经元。我们的工作确定REST/NRSF是成人神经干细胞分化的主要负调控因子，并为神经再生方法提供了一个潜在的分子靶点。
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 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.