Understanding the role of the Glycine Cleavage System in Neural Tube Defects

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Neural tube defects (NTDs) are common birth defects that arise in early pregnancy caused by incomplete formation of the neural tube, which will later develop into the brain and spinal cord. As a result, the brain and/or spinal cord of the fetus become irreversibly damaged, resulting in death around birth, or long term disability in surviving children. The most common forms of NTDs are anencephaly, affecting the brain, and spina bifida, which affects the lower spinal cord. They occur in approximately 1-2 per 1,000 pregnancies and total at least 170,000 new cases per year worldwide.The risk of NTDs depends on both inherited factors and environmental influences such as maternal diet, diabetes or exposure to certain chemicals. Because of the many possible contributory factors, the exact causes of NTDs in any affected individual are usually unknown. However, the risk of an affected pregnancy can be substantially reduced if the mother takes folic acid supplements before and during early pregnancy. Unfortunately, not all NTDs are prevented by folic acid - perhaps up to 50% of all cases fail to respond - and so additional therapies are needed. In order to make further progress towards prevention of all NTDs we need a better understanding of their causes, in particular the genes that increase a person's risk of NTD. Moreover, it will be important to identify new preventive therapies for NTDs which may be used individually or in combination with folic acid. In families where genetic risk factors have been identified this also means that family-specific therapies may be offered.All cells require efficient handling of small molecules called folates, which are related to folic acid, for many different functions. It appears that some NTDs are caused by an inherited abnormality in the way cells in the embryo handle folates. We studied a group of proteins called the "glycine cleavage system" (GCS), that are involved in folate handling. Some patients with NTDs had defects in these proteins, whereas unaffected people did not. This finding suggests that problems with the GCS may directly cause NTDs. In support of this idea, mouse embryos that have GCS defects also develop NTDs.This project will make use of mouse models lacking function of glycine decarboxylase (Gldc), part of the GCS. The mouse models provide an opportunity to study the role of these folate handling proteins in the embryo and how the associated NTDs may be prevented. We have found that handling of folates is altered in Gldc-deficient embryos and we will now use detailed metabolic studies to work out exactly how these changes come about. We will use genetic approaches to turn off Gldc function or to restore function only in the neural tube. This will tell us which tissues in the developing embryo need Gldc function, to ensure normal development.The next step is to understand which of the outputs of folate metabolism are disrupted in Gldc-deficient embryos and to test which of the changes are responsible for NTDs. This will be achieved by detailed biochemical analysis and embryo imaging using markers of particular cellular changes, followed by use of supplements to correct these defects. Folate metabolism is essential for synthesis of DNA, which is needed for cells to divide, and methylation reactions that modify gene expression and other functions. Folate metabolism may also be needed for regulation of the level of reactive oxygen species (free radicals) which can be damaging within cells. An imbalance in production and removal of these molecules, termed oxidative stress, is important in a number of diseases, including diabetes. We will examine whether Gldc-deficiency causes oxidative stress in developing embryos, that may contribute to NTDs.Understanding the molecular and cellular causes of NTDs in Gldc-deficient embryos is an important step towards developing new therapies to prevent more NTDs in humans than is currently possible using folic acid alone.