MiR-302 Regulates Glycolysis to Control Cell-Cycle during Neural Tube Closure.
MiR-302 Regulates Glycolysis to Control Cell-Cycle during Neural Tube Closure.
复制标题
在神经管闭合过程中，miR - 302通过调控糖酵解来控制细胞周期。
DOI：
10.3390/ijms21207534
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发表时间：
2020-10-13
影响因子：
5.6
通讯作者：
Parchem RJ
中科院分区：
文献类型：
--
作者：
Keuls RA;Kojima K;Lozzi B;Steele JW;Chen Q;Gross SS;Finnell RH;Parchem RJ
神经管闭合是中枢神经系统发育的关键早期步骤，需要精确控制代谢以确保适当的细胞增殖和分化。妊娠期间葡萄糖代谢失调与人类神经管闭合缺陷（NTDs）有关，这表明发育中的神经上皮对代谢变化特别敏感。然而，目前尚不清楚在神经发育过程中代谢途径是如何调节的。在这里，我们使用单细胞mrna测序来分析小鼠神经发育过程中参与碳、脂肪、维生素和抗氧化剂代谢的基因表达，并确定糖酵解和细胞增殖的耦合，以确保适当的神经管闭合。使用miR-302缺失作为颅骨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。这些发现通过基于质谱的代谢物分析得到了验证，发现糖酵解增加，脂质代谢物减少，这与miR-302缺失后中心碳交通的重新布线一致。预测的miR-302靶点Pfkp、Pfkfb3和Hk1在NTD时显著上调，导致糖酵解通量增加、细胞周期缩短和增殖增加。我们的研究结果确定了miR-302在协调神经管闭合的代谢景观中的关键作用。
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 miR-302 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 miR-302. Predicted miR-302 targets Pfkp, Pfkfb3, and Hk1 are significantly upregulated upon NTD resulting in increased glycolytic flux, a shortened cell cycle, and increased proliferation. Our findings establish a critical role for miR-302 in coordinating the metabolic landscape of neural tube closure.
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影响因子：
2.5
作者：
Boot, MJ;Steegers-Theunissen, RPM;Gittenberger-de Groot, AC
通讯作者：
Gittenberger-de Groot, AC
影响因子：
5.6
作者：
Becker, Klaus A.;Ghule, Prachi N.;Stein, Gary S.
通讯作者：
Stein, Gary S.
影响因子：
29
作者：
Folmes CD;Nelson TJ;Martinez-Fernandez A;Arrell DK;Lindor JZ;Dzeja PP;Ikeda Y;Perez-Terzic C;Terzic A
通讯作者：
Terzic A
影响因子：
10.5
作者：
Gottlob, K;Majewski, N;Hay, N
通讯作者：
Hay, N
DOI：
10.1073/pnas.96.6.3047
发表时间：
1999-03-16
影响因子：
11.1
作者：
Chesney, J;Mitchell, R;Bucala, R
通讯作者：
Bucala, R