Laboratory for Molecular Neurobiology, Faculty of Human Sciences, Waseda University, Tokorozawa, Saitama 359-1192, Japan.
Laboratory for Molecular Neurobiology, Faculty of Human Sciences, Waseda University, Tokorozawa, Saitama 359-1192, Japan
eNeuro. 2023 Oct 10;10(10). doi: 10.1523/ENEURO.0159-23.2023. Print 2023 Oct.
The levels of purines, essential molecules to sustain eukaryotic cell homeostasis, are regulated by the coordination of the and salvage synthesis pathways. In the embryonic central nervous system (CNS), the pathway is considered crucial to meet the requirements for the active proliferation of neural stem/progenitor cells (NSPCs). However, how these two pathways are balanced or separately used during CNS development remains poorly understood. In this study, we showed a dynamic shift in pathway utilization, with greater reliance on the pathway during embryonic stages and on the salvage pathway in postnatal-adult mouse brain. The pharmacological effects of various purine synthesis inhibitors and the expression profile of purine synthesis enzymes indicated that NSPCs in the embryonic cerebrum mainly use the pathway. Simultaneously, NSPCs in the cerebellum require both the and the salvage pathways. administration of inhibitors resulted in severe hypoplasia of the forebrain cortical region, indicating a gradient of purine demand along the anteroposterior axis of the embryonic brain, with cortical areas of the dorsal forebrain having higher purine requirements than ventral or posterior areas such as the striatum and thalamus. This histologic defect of the neocortex was accompanied by strong downregulation of the mechanistic target of rapamycin complex 1 (mTORC1)/ribosomal protein S6 kinase (S6K)/S6 signaling cascade, a crucial pathway for cell metabolism, growth, and survival. These findings indicate the importance of the spatiotemporal regulation of both purine pathways for mTORC1 signaling and proper brain development.
嘌呤水平是维持真核细胞内环境稳定的必需分子，它们的水平受到补救合成途径和从头合成途径的协调调节。在胚胎中枢神经系统 (CNS) 中，从头合成途径被认为对满足神经干细胞/祖细胞 (NSPCs) 的活跃增殖需求至关重要。然而，这两条途径在 CNS 发育过程中是如何平衡或分别被利用的，目前仍知之甚少。在本研究中，我们发现途径利用发生了动态变化，胚胎期更依赖于从头合成途径，而在出生后成年期的小鼠大脑中则更依赖于补救合成途径。各种嘌呤合成抑制剂的药理学作用以及嘌呤合成酶的表达谱表明，胚胎大脑中的 NSPCs 主要利用从头合成途径。同时，小脑中的 NSPCs 需要从头合成途径和补救合成途径。嘌呤合成抑制剂的给药导致前脑皮质区域严重发育不良，表明胚胎大脑的前后轴上存在嘌呤需求的梯度，背侧前脑皮质区域的嘌呤需求高于纹状体和丘脑等腹侧或后侧区域。这种新皮质的组织学缺陷伴随着雷帕霉素靶蛋白复合物 1 (mTORC1)/核糖体蛋白 S6 激酶 (S6K)/S6 信号级联的强烈下调，mTORC1 信号通路是细胞代谢、生长和存活的关键途径。这些发现表明，嘌呤途径的时空调节对 mTORC1 信号和大脑的正常发育非常重要。
