Development, Disease Models & Therapeutics Graduate Program, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Center for Cell and Gene Therapy, Stem Cells and Regenerative Medicine Center, One Baylor Plaza, Houston, TX 77030, USA.
Int J Mol Sci. 2020 Oct 13;21(20):7534. doi: 10.3390/ijms21207534.
Neural tube closure is a critical early step in central nervous system development that requires precise control of metabolism to ensure proper cellular proliferation and differentiation. Dysregulation of glucose metabolism during pregnancy has been associated with neural tube closure defects (NTDs) in humans suggesting that the developing neuroepithelium is particularly sensitive to metabolic changes. However, it remains unclear how metabolic pathways are regulated during neurulation. Here, we used single-cell mRNA-sequencing to analyze expression of genes involved in metabolism of carbon, fats, vitamins, and antioxidants during neurulation in mice and identify a coupling of glycolysis and cellular proliferation to ensure proper neural tube closure. Using loss of as a genetic model of cranial NTD, we identify misregulated metabolic pathways and find a significant upregulation of glycolysis genes in embryos with NTD. These findings were validated using mass spectrometry-based metabolite profiling, which identified increased glycolytic and decreased lipid metabolites, consistent with a rewiring of central carbon traffic following loss of . Predicted targets , , and are significantly upregulated upon NTD resulting in increased glycolytic flux, a shortened cell cycle, and increased proliferation. Our findings establish a critical role for in coordinating the metabolic landscape of neural tube closure.
神经管闭合是中枢神经系统发育的一个关键早期步骤，需要精确控制代谢以确保细胞的适当增殖和分化。妊娠期间葡萄糖代谢的失调与人类神经管闭合缺陷（NTD）有关，这表明发育中的神经上皮对代谢变化特别敏感。然而，代谢途径在神经胚形成过程中是如何被调节的仍不清楚。在这里，我们使用单细胞 mRNA 测序来分析在小鼠神经管闭合过程中参与碳、脂肪、维生素和抗氧化剂代谢的基因的表达，并确定糖酵解和细胞增殖的偶联以确保适当的神经管闭合。使用作为颅 NTD 的遗传模型，我们确定了代谢途径的失调，并发现 NTD 胚胎中糖酵解基因的显著上调。使用基于质谱的代谢物谱分析对这些发现进行了验证，该分析鉴定出糖酵解和脂质代谢物减少，这与 缺失后中心碳流量的重新布线一致。预测的 靶基因 、 和 在 NTD 后显著上调，导致糖酵解通量增加、细胞周期缩短和增殖增加。我们的研究结果确立了 在协调神经管闭合的代谢景观中的关键作用。
