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Abstract：
During development, neural stem cells in the cerebral cortex, also known as radial glial cells (RGCs), generate excitatory neurons, followed by production of cortical macroglia and inhibitory neurons that migrate to the olfactory bulb (OB). Understanding the mechanisms for this lineage switch is fundamental for unraveling how proper numbers of diverse neuronal and glial cell types are controlled. We and others recently showed that Sonic Hedgehog (Shh) signaling promotes the cortical RGC lineage switch to generate cortical oligodendrocytes and OB interneurons. During this process, cortical RGCs generate intermediate progenitor cells that express critical gliogenesis genes Ascl1, Egfr, and Olig2. The increased Ascl1 expression and appearance of Egfr+ and Olig2+ cortical progenitors are concurrent with the switch from excitatory neurogenesis to gliogenesis and OB interneuron neurogenesis in the cortex. While Shh signaling promotes Olig2 expression in the developing spinal cord, the exact mechanism for this transcriptional regulation is not known. Furthermore, the transcriptional regulation of Olig2 and Egfr has not been explored. Here, we show that in cortical progenitor cells, multiple regulatory programs, including Pax6 and Gli3, prevent precocious expression of Olig2, a gene essential for production of cortical oligodendrocytes and astrocytes. We identify multiple enhancers that control Olig2 expression in cortical progenitors and show that the mechanisms for regulating Olig2 expression are conserved between the mouse and human. Our study reveals evolutionarily conserved regulatory logic controlling the lineage switch of cortical neural stem cells.
摘要：
在开发过程中,大脑皮层中的神经干细胞，也称为放射状神经胶质细胞（RGC），产生兴奋性神经元，随后产生皮质大胶质细胞和迁移到嗅球（OB）的抑制性神经元。了解这种谱系转换的机制对于揭示如何控制适当数量的各种神经元和神经胶质细胞类型至关重要。我们和其他人最近表明，SonicHedgehog（Shh）信号促进皮质RGC谱系转换以产生皮质少突胶质细胞和OB中间神经元。在这个过程中,皮质RGCs产生表达关键神经胶质发生基因Ascl1，Egfr，Olig2Egfr和Olig2皮质祖细胞的Ascl1表达增加和出现与皮质中的兴奋性神经发生向神经胶质发生和OB中间神经元神经发生的转变同时发生。而Shh信号促进Olig2在发育中的脊髓表达，这种转录调控的确切机制尚不清楚。此外，Olig2和Egfr的转录调控尚未被探索。这里,我们发现在皮质祖细胞中，多个监管计划，包括Pax6和Gli3，阻止Olig2的早熟表达，Olig2是产生皮质少突胶质细胞和星形胶质细胞所必需的基因。我们确定了控制皮质祖细胞中Olig2表达的多种增强子，并表明调节Olig2表达的机制在小鼠和人之间是保守的。我们的研究揭示了控制皮质神经干细胞谱系转换的进化保守的调节逻辑。
