NYU Neuroscience Institute, Langone Medical Center, New York, New York 10016, USA.
New York Genome Center, New York, New York 10013, USA.
Nature. 2018 Mar 22;555(7697):457-462. doi: 10.1038/nature25999. Epub 2018 Mar 5.
Diverse subsets of cortical interneurons have vital roles in higher-order brain functions. To investigate how this diversity is generated, here we used single-cell RNA sequencing to profile the transcriptomes of mouse cells collected along a developmental time course. Heterogeneity within mitotic progenitors in the ganglionic eminences is driven by a highly conserved maturation trajectory, alongside eminence-specific transcription factor expression that seeds the emergence of later diversity. Upon becoming postmitotic, progenitors diverge and differentiate into transcriptionally distinct states, including an interneuron precursor state. By integrating datasets across developmental time points, we identified shared sources of transcriptomic heterogeneity between adult interneurons and their precursors, and uncovered the embryonic emergence of cardinal interneuron subtypes. Our analysis revealed that the transcription factor Mef2c, which is linked to various neuropsychiatric and neurodevelopmental disorders, delineates early precursors of parvalbumin-expressing neurons, and is essential for their development. These findings shed new light on the molecular diversification of early inhibitory precursors, and identify gene modules that may influence the specification of human interneuron subtypes.
皮质中间神经元的不同亚群在高级脑功能中起着至关重要的作用。为了研究这种多样性是如何产生的,我们在这里使用单细胞 RNA 测序来描述沿着发育时间过程收集的小鼠细胞的转录组。神经节隆起中的有丝分裂祖细胞的异质性是由高度保守的成熟轨迹驱动的,伴随着隆起特异性转录因子表达,为后来的多样性的出现奠定基础。成为有丝分裂后,祖细胞开始分化,并分化为转录上不同的状态,包括中间神经元前体细胞状态。通过整合跨发育时间点的数据集,我们确定了成年中间神经元与其前体细胞之间转录组异质性的共同来源,并揭示了主要中间神经元亚型在胚胎中的出现。我们的分析表明,转录因子 Mef2c 与各种神经精神和神经发育障碍有关,它划定了表达 parvalbumin 的神经元的早期前体细胞,并对其发育至关重要。这些发现为早期抑制性前体细胞的分子多样化提供了新的线索,并确定了可能影响人类中间神经元亚型特异性的基因模块。