Neural tube defects (NTDs), among the most common birth defects in humans, are believed to have multifactorial causes. One of the strongest links to modifying NTD susceptibility is to maternal folic acid status. However, the biochemical mechanisms that underlie these folate-dependent processes are not understood. This gap in our knowledge hinders our ability to make informed health policy decisions about folic acid fortification and prevention of NTDs and other human diseases, both congenital and those occurring later in life. My long term goal is to understand the mechanisms by which folic acid supports normal neural tube development, and how altered folate metabolism leads to the development of NTDs. The objective of this proposal is to identify the mechanism(s) by which loss of a specific folate-dependent enzyme (mitochondrial MTHFD1L) leads to NTDs. My central hypothesis is that the NTDs observed in the Mthfd1l nullizygous mouse are caused by defects in mitochondrial folate-dependent one-carbon (1C) metabolism, which supplies 1C units for essential processes such as de novo purine, thymidylate, glycine, and methyl group biosynthesis. The rationale for this research is that the Mthfd1l mouse model provides a unique opportunity to discover the specific metabolic mechanism(s) that underlie the folate dependence of normal neural tube development. More importantly, a better mechanistic understanding is likely to lead to new and innovative approaches to folate fortification or other therapeutic interventions in the effort to reduce or prevent NTDs in humans. I will test my central hypothesis, and thereby accomplish the objective of this proposal, through one Specific Aim: Identify the biochemical defects responsible for neural tube defects in Mthfd1l nullizygous embryos. Under this aim, I will use biochemical assays to analyze the folate-dependent metabolic processes in normal (+/+), heterozygous (+/-), and nullizygous (-/-) embryos and in embryonic stem (ES) cells derived from the three Mthfd1l genotypes. The expected outcome of this aim is the identification of specific metabolic mechanisms responsible for the NTDs observed in Mthfd1l nullizygous embryos. The research proposed in this application is innovative, in my opinion, because it focuses on a new mouse NTD model (Mthfd1l knockout) that closely replicates the human NTD phenotype, and does not require additional nutritional intervention to express the disease phenotype. Moreover, a common variant of human Mthfd1l has been shown to be associated with increased risk of NTDs in some populations. This contribution is significant because identification of specific metabolic mechanisms will fundamentally advance understanding of folate-responsive NTDs, and will provide much needed new insight into non-folate-responsive NTDs as well. This detailed mechanistic information will be essential as we evaluate the efficacy and safety of the current folic acid fortification program in reducing the prevalence of human NTDs.

Public Health Relevance

The proposed research is relevant to public health because while we know that dietary supplementation with folic acid reduces the incidence of neural tube defects;the mechanism behind this protection is very poorly understood. Understanding the link between this gene and development of neural tube defects will provide a mechanistic link between these devastating birth defects and folate metabolism. Thus, the proposed research is relevant to NIH's mission of increasing our understanding of life processes to lay the foundation for advances in disease diagnosis, treatment and prevention.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F06-T (20))
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Henken, Deborah B
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University of Texas Austin
Schools of Arts and Sciences
United States
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Shin, Minhye; Bryant, Joshua D; Momb, Jessica et al. (2014) Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues. J Biol Chem 289:15507-17
Momb, Jessica; Appling, Dean R (2014) Mitochondrial one-carbon metabolism and neural tube defects. Birth Defects Res A Clin Mol Teratol 100:576-83