Developmental emergence of adult neural stem cells as revealed by single cell transcriptional profiling

Adult neural stem cells (NSCs) derive from embryonic precursors, but little is known about how or when this occurs. We have addressed this issue using single cell RNAseq at multiple developmental timepoints to analyze the embryonic murine cortex, one source of adult forebrain NSCs. We computationally identify all major cortical cell types, including the embryonic radial precursors (RPs) that generate adult NSCs. We define the initial emergence of RPs from neuroepithelial stem cells at E11.5. We show that by E13.5 these RPs express a transcriptional identity that is maintained and reinforced throughout their transition to a non-proliferative state between E15.5 and E17.5. These slowly-proliferating late embryonic RPs share a core transcriptional phenotype with quiescent adult forebrain NSCs. Together, these findings support a model where cortical RPs maintain a core transcriptional identity from embryogenesis through to adulthood, and where the transition to a quiescent adult NSC occurs during late neurogenesis. We applied the high-throughput single-cell mRNA sequencing technique, Drop-seq, to the embryonic mouse cortex. 2000-5000 single cells from wildtype CD1 embryos of gestational ages E11.5, E13.5, E15.5 and E17.5 were characterized.成年神经干细胞（neural stem cells, NSCs）源自胚胎前体细胞，但目前学界对其产生的具体机制与时间节点仍所知有限。本研究借助多发育时间点的单细胞RNA测序技术，对成年前脑神经干细胞的来源之一——胚胎小鼠皮层开展分析，以解答这一科学问题。 研究通过计算分析鉴定出所有主要皮层细胞类型，其中包括生成成年NSCs的胚胎放射状前体细胞（radial precursors, RPs）。本研究明确了RPs于胚胎日龄E11.5时从神经上皮干细胞中初始出现。研究证实，至E13.5时，这些RPs已具备一套特异性转录组特征，并在其于E15.5至E17.5间过渡至非增殖状态的过程中，该特征得以维持并进一步强化。这些增殖速率缓慢的晚期胚胎RPs，与静息成年前脑神经干细胞共享一套核心转录组表型。综上，本研究结果支持如下模型：皮层RPs从胚胎发生阶段直至成年阶段，始终维持一套核心转录组特征；而向静息成年NSCs的转变过程，发生于晚期神经发生阶段。 本研究采用高通量单细胞mRNA测序技术Drop-seq，对胚胎小鼠皮层进行样本检测。研究对孕龄为E11.5、E13.5、E15.5及E17.5的野生型CD1品系胚胎，各选取2000~5000个单细胞进行了特征鉴定与分析。