Department of Neurobiology and Behavior, and Howard Hughes Medical Institute, State University of New York, Stony Brook, NY 11794, USA.
Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16789-94. doi: 10.1073/pnas.1113486108. Epub 2011 Sep 15.
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.
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），调节新皮层发育过程中的放射状迁移和神经祖细胞分化的时间，并且调节取决于 REST 水平的差异。具体而言，REST 的持续存在会阻止迁移并极大地延迟——但不会阻止——神经元分化，导致类似于双皮质蛋白缺失的皮质下带异位样表型。我们进一步表明，双皮质蛋白是 REST 的直接靶基因，并且其过表达至少部分挽救了由 REST 持续存在引起的异常表型。我们的研究支持这样一种观点，即神经祖细胞中 REST 的靶向下调至低水平，以及随后在神经发生过程中消失，对于调节神经祖细胞向神经元的时空过渡的时间至关重要。
