Abstract
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.
Highlights
Neural tube closure is a critical first step in the formation of the central nervous system and requires precise cell growth, movement, and organization [1,2,3,4,5,6,7,8,9,10,11,12,13]
We focused on ectoderm-derived cell populations that contribute to neural tube closure, including fore, mid, and hind-brain tissues of the central nervous system, the neural crest lineage, and non-neural ectoderm (Figure 1A)
Since we found an enrichment for metabolism genes in the developing neural tube and Neural tube closure defects (NTDs) result from changes in energy metabolism and redox state of the cell, we analyzed how the expression of genes involved in fatty acid metabolism, antioxidant activity, oxidative phosphorylation, glycolysis, and folic acid metabolism change over time during neural tube closure in a cell and tissue-specific manner
Summary
Neural tube closure is a critical first step in the formation of the central nervous system and requires precise cell growth, movement, and organization [1,2,3,4,5,6,7,8,9,10,11,12,13]. NTDs in humans have been associated with changes in the oxidative state of cells within the developing neural tube resulting from exposure to teratogens, such as excess glucose in the context of maternal diabetes [24,25,26,27,28,29]. How increased glucose and oxidative state changes affect fetal metabolism and increase NTD risk has not been fully elucidated
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