Antisense modulation of 5,10-methylenetetrahydrofolate reductase expression produces neural tube defects in mouse embryos

The role of folate metabolism in producing neural tube defects (NTDs) in hu mans is unknown. In the current study, antisense oligodeoxyribonucleotide t echnology was utilized to disrupt normal expression of the gene for 5,10-me thylenetrtrahydrofolate reductase (MTHFR) in organogenesis-stage mouse embr yos. Two different antisense probes were microinjected into the amniotic sa c of gestation day (CD) 8 mouse embryos with PBS or scrambled sense oligode oxyribonucleotides injected into control embryos. Concentration-dependent i ncreases in the frequencies of embryos with NTDs were observed for both ant isense sequences. The level of mRNA for MTHFR was decreased in embryos trea ted with the higher concentration of one antisense sequence, indicating tha t the sequence is able to decrease gene expression. 5-methyltetrahydrofolat e, the product of the MTHFR reaction, was able to decrease the incidence of antisrnse-induced NTDs, but co-injection with L-methionine did not. These results suggest that reduced expression of MTHFR may play a role in produci ng NTDs:. (C) 2001 Elsevier Science Inc. All rights reserved.