Disruption of Mitochondrial Folate Transporter Gene (Slc25A32) Induces Embryonic Lethality and Neural Tube Defects in Mice

Abstract

Neural tube defects (NTDs) are among the most common birth defects in humans. The causes of NTDs are thought to be multifactorial, including genetic, environmental, and nutritional factors. Multiple studies have shown that periconceptional supplementation with folic acid can reduce the incidence of NTDs. Despite more than 40 years of intensive effort, we still do not understand the mechanisms that underlie these folate‐dependent processes. Having a long‐standing interest in transport systems involved in one carbon metabolism, we developed a new mouse NTD model by knocking out the mitochondrial folate transporter MFT (Slc25A32) gene. MFT is an inner mitochondrial membrane protein that transports folates into mitochondria. In the inner mitochondrial membrane, MFT mediates the reversible transport of tetrahydrofolate (THF) between the cytosol and the mitochondrial matrix and plays a role in maintaining folate concentration within the cell.To examine the function of MFT during embryonic development, embryos had been dissected from heterozygous pregnant MFT+/− dams between E10.5‐E12.5. We analyzed the phenotypes of MFT knockout embryos from heterozygous MFT+/− breeding pairs. All nullizygous MFT−/−embryos exhibited 100% penetrant neural tube defects that were confined mostly to the head region and sometimes extending to the cervical or thoracic region. We determined that loss of a specific folate‐dependent transport protein leads to NTDs and this new mouse model provides insight to understand a folate‐specific transport mechanism of the MFT that underlie folate dependent process of NTD.Support or Funding InformationSupported in part by National Institutes of Health (NIH) grants HD067244, ES021006, and NS076465 to RHF.