Maternal metabolism influences neural tube closure

Abstract

Changes in maternal nutrient availability due to diet or disease significantly increase the risk of neural tube defects (NTDs). Because the incidence of metabolic disease continues to rise, it is urgent that we better understand how altered maternal nutrient levels can influence embryonic neural tube development. Furthermore, primary neurulation occurs before placental function during a period of histiotrophic nutrient exchange. In this review we detail how maternal metabolites are transported by the yolk sac to the developing embryo. We discuss recent advances in understanding how altered maternal levels of essential nutrients disrupt development of the neuroepithelium, and identify points of intersection between metabolic pathways that are crucial for NTD prevention.

Keywords: folate; glucose; maternal–fetal communication; neural tube; yolk sac.

Figure 1.. Timing of primary neurulation varies across mouse and human development.

[A] Diagram of implantation and neurulation stages in mouse and [B] human embryos. During mouse development, closure 1 initiates in embryos with 5 somites during embryonic day E8.5 and is completed on embryonic day E10.5 (29–30 somites). The timing of closure 2 is variable across mouse strains and closure 3 initiates in embryos with 10 somites and is completed at 19–20 somites. In human embryos, closure 1 initiates at 4–6 somites and spreads to mesencephalic and thoracic levels by 12–13 somites. Closure 3 is complete in human embryos with 19–20 somites [–12].

Figure 2.. Folic acid, glucose, and fatty acids are maternally supplied metabolites

Abbreviated folate, glucose, fatty acid, and cholesterol metabolic pathways. The folate cycle occurs in the cytosol, nucleus, and mitochondria. Enzymes are listed for the processing of tetrahydrofolate and 5,10-Methylenetetrahydrofolate in each subcellular location outlined by dashed boxes. The intersection between glycolysis and folate metabolism is due to the conversion between 3-phosphoglycerate and serine. The intersection between glycolysis and fatty acid pathways is due to the production of intermediates acetyl-CoA and citrate that can serve as input in each pathway. Points of intersection between metabolic pathways are bolded and labeled in red.

Figure 3.. Histiotrophic nutrient exchange during neural tube closure

[A] Organization of histiotrophic tissues during primary neurulation stages of mouse and [B] human development [81,105].

Figure 4.. Altered levels of essential nutrients disrupt neuroepithelial morphogenesis.

[A] Scanning electron microscopy of an embryo with a closed neural tube and an embryo with an NTD. [B] Folic acid deficiency results in a proposed disruption in dorsal/ventral neuroepithelial patterning, altered levels of methylation resulting in increased genome instability. [C] Maternal diabetes may result in microvilli lengthening and a disruption in the balance between cellular proliferation and differentiation.