Embryonic folate metabolism and mouse neural tube defects.
Folic acid prevents 70 percent of human neural tube defects (NTDs) but its mode of action is unclear. The deoxyuridine suppression test detects disturbance of folate metabolism in homozygous splotch (Pax3) mouse embryos that are developing NTDs in vitro. Excessive incorporation of [3H]thymidine in splotch embryos indicates a metabolic deficiency in the supply of folate for the biosynthesis of pyrimidine. Exogenous folic acid and thymidine both correct the biosynthetic defect and prevent some NTDs in splotch homozygotes, whereas methionine has an exacerbating effect. These data support a direct normalization of neurulation by folic acid in humans and suggest a metabolic basis for folate action.
Fleming
A
A
Neural Development Unit, Institute of Child Health, University College London, London WC1N 1EH, UK.
Copp
A J
AJ
D000818:Animals; D002490:Central Nervous System / Q000196:embryology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003856:Deoxyuracil Nucleotides / Q000378:metabolism / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000378:metabolism*; D005260:Female; D005492:Folic Acid / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008297:Male; D008715:Methionine / Q000494:pharmacology; D051379:Mice; D008808:Mice, Inbred CBA; D009154:Mutation; D009436:Neural Tube Defects / Q000196:embryology / Q000209:etiology* / Q000517:prevention & control*; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D011743:Pyrimidines / Q000096:biosynthesis; D013763:Tetrahydrofolates / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism / Q000494:pharmacology; D013938:Thymidine Monophosphate / Q000378:metabolism; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D003856:Deoxyuracil Nucleotides; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D011743:Pyrimidines; D013763:Tetrahydrofolates; D014157:Transcription Factors; C013123:5,10-methylenetetrahydrofolic acid; C068686:Pax3 protein, mouse; D013938:Thymidine Monophosphate; D005492:Folic Acid; C007267:2'-deoxyuridylic acid; D008715:Methionine; D013936:Thymidine