一碳/叶酸代谢为DNA和组蛋白甲基化提供了所需的甲基基团，并参与了干细胞的自我更新。在新皮质发育的早期阶段，二氢叶酸还还原酶(DHFR)在人类和小鼠的神经祖细胞中高度表达。在本研究中，我们探究了DHFR在新皮质发育中的作用，并报告了在人类神经体外器官和小鼠胚胎新皮质中降低其活性会加速间接神经发生，从而影响新皮质的神经元组成。此外，我们还展示了在神经祖细胞中降低DHFR活性会导致一碳/叶酸代谢产物的减少，并与H3K4me3水平的修饰相关。我们的研究结果揭示了DHFR在控制新皮质发育特定步骤中的意外作用，并表明一碳代谢信号的变化影响细胞命运的转变。© 2023. 由生物学家公司出版。

One-carbon/folate (1C) metabolism supplies methyl groups required for DNA and histone methylation, and is involved in the maintenance of self-renewal in stem cells. Dihydrofolate reductase (DHFR), a key enzyme in 1C metabolism, is highly expressed in human and mouse neural progenitors at the early stages of neocortical development. Here, we have investigated the role of DHFR in the developing neocortex and report that reducing its activity in human neural organoids and mouse embryonic neocortex accelerates indirect neurogenesis, thereby affecting neuronal composition of the neocortex. Furthermore, we show that decreasing DHFR activity in neural progenitors leads to a reduction in one-carbon/folate metabolites and correlates with modifications of H3K4me3 levels. Our findings reveal an unanticipated role for DHFR in controlling specific steps of neocortex development and indicate that variations in 1C metabolic cues impact cell fate transitions.© 2023. Published by The Company of Biologists Ltd.