Human neurodevelopment is slower than that of other mammalian species, and this timescale appears to be intrinsic to human neural cells. However, not much is known about the mechanisms that govern this maturational timing. In a recent paper in Nature, Ciceri et al. developed a human pluripotent stem cell culture protocol that synchronously generates a uniform population of cortical neurons. The authors followed the slow course of the neurons’ maturation over 100 days using genomic, physiological and morphological assays. They then used CRISPR–Cas9 to knockout 21 transcriptional regulators whose expression steadily decreased over the 100 days of development in culture, and screened for indications of accelerated maturation. They found that pharmacologically inhibiting the epigenetic regulators identified in the screen (EZH2, DOT1L, and EHMT1/EHMT2) at the earlier neural progenitor cell stage lastingly sped up later neuronal maturation. They interpret this to mean that the slow maturation rate of human neurons is determined by an epigenetic brake that is engaged even before neurogenesis.

Original reference: Nature, https://doi.org/10.1038/s41586-023-06984-8 (2024)

人类神经发育比其他哺乳动物物种慢，并且这个时间尺度似乎是人类神经细胞固有的。然而，人们对控制这种成熟时间的机制知之甚少。在《自然》杂志最近发表的一篇论文中，Ciceri 等人。开发了一种人类多能干细胞培养方案，可同步生成均匀的皮质神经元群。作者利用基因组、生理学和形态学分析追踪了神经元在 100 多天内成熟的缓慢过程。然后，他们使用 CRISPR-Cas9 敲除 21 个转录调节因子，这些调节因子的表达在培养物发育的 100 天中稳步下降，并筛选加速成熟的迹象。他们发现，在早期神经祖细胞阶段通过药理学抑制筛选中发现的表观遗传调节因子（EZH2、DOT1L 和 EHMT1/EHMT2）可持久加速后期神经元的成熟。他们将此解释为人类神经元成熟速度缓慢是由表观遗传制动决定的，这种制动甚至在神经发生之前就已发生。

原文参考： 《自然》，https://doi.org/10.1038/s41586-023-06984-8 (2024)