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)