Repressor element 1 silencing transcription factor (REST) controls radial migration and temporal neuronal specification during neocortical development
Repressor element 1 silencing transcription factor (REST) controls radial migration and temporal neuronal specification during neocortical development
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DOI：
10.1073/pnas.1113486108
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发表时间：
2011-10-04
影响因子：
11.1
通讯作者：
Ballas, Nurit
中科院分区：
文献类型：
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作者：
Mandel, Gail;Fiondella, Christopher G.;Ballas, Nurit
神经发生需要协调早期细胞命运决定、迁移和终末分化的机制。在这里，我们表明，转录抑制因子，抑制元件1沉默转录因子（REST），调节径向迁移和神经祖细胞分化的时间在新皮层发育过程中，和该调节是偶然的差异REST水平。具体而言，REST的持续存在会阻止迁移，并大大延迟-但不能阻止-神经元分化，导致皮质下带状异位样表型，让人想起doublecortin的丢失。我们进一步表明，doublecortin是REST的直接基因靶点，并且其过表达至少部分地挽救了由REST持续存在引起的异常表型。我们的研究支持这样的观点：在神经祖细胞中将REST定向下调至低水平，以及随后在神经发生期间消失，对于神经祖细胞向神经元的时空转变的时机至关重要。
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.