In the developing nervous system, progenitors first generate neurons before making astrocytes and oligodendrocytes. We previously showed that increased Sonic hedgehog (Shh) signaling in dorsal forebrain progenitors is important for their production of oligodendrocytes as neurogenesis winds down. Here, we analyzed single-cell RNA sequencing datasets to better understand how Shh controls this neuron-to-oligodendrocyte switch in the neocortex. We first identified Shh-responding progenitors using a dataset in which Shh was overexpressed in the mouse dorsal forebrain. Pseudotime trajectory inferences revealed a subpopulation committed to the oligodendrocyte precursor cell (OPC) lineage. Genes upregulated along this lineage defined a pre-OPC state, as cells transitioned from progenitors to OPCs. Using several datasets from wild-type mouse and human embryos at different ages, we confirmed a pre-OPC state preceding OPC emergence during normal development. Finally, we show that pre-OPCs are enriched for a gene regulatory network involving the transcription factor Ascl1. Genetic lineage-tracing demonstrated Ascl1-positive dorsal progenitors primarily make oligodendrocytes. We propose a model in which Shh shifts the balance between opposing transcriptional networks toward an Ascl1 lineage, thereby facilitating the switch between neurogenesis and oligodendrogenesis.

中文翻译：

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揭示声波刺猬反应性新皮层祖细胞中驱动少突胶质细胞命运规范的转录网络

在发育中的神经系统中，祖细胞先生成神经元，然后再生成星形胶质细胞和少突胶质细胞。我们先前显示，随着神经发生的减弱，背侧前脑祖细胞中Sonic刺猬（Shh）信号的增加对于其少突胶质细胞的产生非常重要。在这里，我们分析了单细胞RNA测序数据集，以更好地了解Shh如何控制新皮层中这种神经元向少突胶质细胞的转换。我们首先使用在小鼠背前脑中过表达Shh的数据集确定了Shh响应祖细胞。伪时间轨迹推断揭示了一个致力于少突胶质前体细胞（OPC）谱系的亚群。沿该谱系上调的基因定义了OPC之前的状态，因为细胞从祖细胞转变为OPC。使用来自不同年龄的野生型小鼠和人类胚胎的数个数据集，我们确认了正常发育期间OPC出现之前的OPC前状态。最后，我们显示，pre-OPCs丰富了涉及转录因子Ascl1的基因调控网络。遗传谱系追踪表明，Ascl1阳性背祖细胞主要产生少突胶质细胞。我们提出了一种模型，其中Shh将相对转录网络之间的平衡移向Ascl1谱系，从而促进神经发生和少突胶质形成之间的转换。遗传谱系追踪表明，Ascl1阳性背祖细胞主要产生少突胶质细胞。我们提出了一种模型，其中Shh将相对转录网络之间的平衡移向Ascl1谱系，从而促进神经发生和少突胶质形成之间的转换。遗传谱系追踪表明，Ascl1阳性背祖细胞主要产生少突胶质细胞。我们提出了一种模型，其中Shh将相对转录网络之间的平衡移向Ascl1谱系，从而促进神经发生和少突胶质形成之间的转换。