Sudiwala, Sonia Jaishri; (2018) Gene-environment interactions in the causation and prevention of neural tube defects. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The aim of the work described in this thesis is to investigate the mechanisms underlying neural tube defects (NTDs), birth defects of the developing central nervous system. The study makes use of mouse models of NTDs, and particularly focuses on the interaction between nutritional factors and genetic risk factors in determining susceptibility to NTDs. In humans some NTDs are preventable by folic acid supplementation, but this is not fully effective so investigation of alternative strategies was a key focus. The efficacy of oral nucleotide and/or inositol supplementation was evaluated for prevention of NTDs in the curly tail (Grhl3 hypomorph) mouse, a model for Folic acid-resistant NTDs. Metabolic effects were investigated by mass spectrometry methods for analysis of folate one-carbon metabolism (FOCM) and nucleotide, nucleoside and nucleobase pools. Genetic factors influencing FOCM in curly tail embryos were investigated, focussing on expression of Mthfd1L, which encodes an enzyme of mitochondrial FOCM. Effects on downstream metabolites and the potential for rescue by supplementation with one-carbon donors was evaluated, together with mass spectrometry based analysis of the treatment. The effect of caffeine on neural tube closure was investigated in several mouse strains to test the hypothesis that caffeine may be a risk factor for NTDs. Caffeine did not interfere with neurulation, and was in fact found to prevent spina bifida in curly tail mice. This prevention was accompanied by changes in embryonic FOCM, and cellular effects were analysed. The cellular basis for prevention of NTDs by folic acid was investigate in the Splotch (Pax3 mutant) mouse. Proliferation was investigated in the cranial neuroepithelium of Splotch mutant and wild-type embryos, under standard and folic acid supplemented conditions. The molecular basis of NTDs was investigated with a focus on abnormal Sonic Hedgehog signalling and disrupted dorso-ventral patterning as potentially contributing to NTDs in Splotch mutants.

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