REST regulates the pool size of the different neural lineages by restricting the generation of neurons and oligodendrocytes from neural stem/progenitor cells
REST regulates the pool size of the different neural lineages by restricting the generation of neurons and oligodendrocytes from neural stem/progenitor cells
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DOI：
10.1242/dev.074765
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发表时间：
2012-08-15
期刊：
影响因子：
4.6
通讯作者：
Ballas, Nurit
中科院分区：
文献类型：
--
作者：
Covey, Matthew V.;Streb, Jeffrey W.;Ballas, Nurit
REST是神经元基因的主要阻遏物;然而，它在神经系统发育过程中是否有任何作用仍然是未知的。在这里，我们系统地分析了REST在胚胎干细胞和多能神经干/祖细胞（NS/P）细胞中的作用，包括来自胚胎干细胞（ES）或发育中的小鼠胚胎的神经源性和胶质源性NS/P细胞。我们发现，REST无效ES细胞保持多能性，并产生由三个胚层组成的畸胎瘤。相比之下，多能NS/P细胞缺乏REST表现出显着降低的自我更新能力，由于减少细胞周期动力学和早熟的神经元分化。重要的是，虽然缺乏REST的早期出生的神经源性NS/P细胞能够分化为神经元和神经胶质细胞，但神经元和少突胶质细胞池显着扩大，星形胶质细胞池缩小。然而，缺乏REST的胶质源性NS/P细胞能够产生正常的星形胶质细胞池大小，这表明缺乏REST的神经源性NS/P细胞产生的星形胶质细胞池的收缩可能默认发生。缺乏REST的早期出生NS/P细胞的微阵列分析显示神经元和少突胶质细胞基因的上调，特别是那些参与髓鞘形成的基因。此外，染色质免疫沉淀分析表明，一些上调的少突胶质细胞基因含有一个RE 1基序，是直接的REST目标。总之，我们的数据支持REST在神经发育过程中促进NS/P细胞自我更新的核心作用，同时限制神经元和少突胶质细胞的生成和成熟。
REST is a master repressor of neuronal genes; however, whether it has any role during nervous system development remains largely unknown. Here, we analyzed systematically the role of REST in embryonic stem cells and multipotent neural stem/progenitor (NS/P) cells, including neurogenic and gliogenic NS/P cells derived from embryonic stem (ES) cells or developing mouse embryos. We showed that REST-null ES cells remained pluripotent and generated teratomas consisting of the three germ layers. By contrast, multipotent NS/P cells lacking REST displayed significantly reduced self-renewal capacity owing to reduced cell cycle kinetics and precocious neuronal differentiation. Importantly, although early-born neurogenic NS/P cells that lack REST were capable of differentiating to neurons and glia, the neuronal and oligodendrocytic pools were significantly enlarged and the astrocytic pool was shrunken. However, gliogenic NS/P cells lacking REST were able to generate a normal astrocytic pool size, suggesting that the shrinkage of the astrocytic pool generated from neurogenic NS/P cells lacking REST probably occurs by default. Microarray profiling of early-born NS/P cells lacking REST showed upregulation of neuronal as well as oligodendrocytic genes, specifically those involved in myelination. Furthermore, chromatin immunoprecipitation analyses showed that some of the upregulated oligodendrocytic genes contain an RE1 motif and are direct REST targets. Together, our data support a central role for REST during neural development in promoting NS/P cell self-renewal while restricting the generation and maturation of neurons and oligodendrocytes.