title: Shmt1 and de novo thymidylate biosynthesis underlie folate-responsive neural tube defects in mice.
abstract: BACKGROUND
  Folic acid supplementation prevents the occurrence and recurrence of neural tube defects (NTDs), but the causal metabolic pathways underlying folic acid-responsive NTDs have not been established. Serine hydroxymethyltransferase (SHMT1) partitions folate-derived one-carbon units to thymidylate biosynthesis at the expense of cellular methylation, and therefore SHMT1-deficient mice are a model to investigate the metabolic origin of folate-associated pathologies.
  
  
  OBJECTIVE
  We examined whether genetic disruption of the Shmt1 gene in mice induces NTDs in response to maternal folate and choline deficiency and whether a corresponding disruption in de novo thymidylate biosynthesis underlies NTD pathogenesis.
  
  
  METHODS
  Shmt1 wild-type, Shmt1(+/-), and Shmt1(-/-) mice fed either folate- and choline-sufficient or folate- and choline-deficient diets were bred, and litters were examined for the presence of NTDs. Biomarkers of impaired folate metabolism were measured in the dams. In addition, the effect of Shmt1 disruption on NTD incidence was investigated in Pax3(Sp) mice, an established folate-responsive NTD mouse model.
  
  
  RESULTS
  Shmt1(+/-) and Shmt1(-/-) embryos exhibited exencephaly in response to maternal folate and choline deficiency. Shmt1 disruption on the Pax3(Sp) background exacerbated NTD frequency and severity. Pax3 disruption impaired de novo thymidylate and purine biosynthesis and altered amounts of SHMT1 and thymidylate synthase protein.
  
  
  CONCLUSIONS
  SHMT1 is the only folate-metabolizing enzyme that has been shown to affect neural tube closure in mice by directly inhibiting folate metabolism. These results provide evidence that disruption of Shmt1 expression causes NTDs by impairing thymidylate biosynthesis and shows that changes in the expression of genes that encode folate-dependent enzymes may be key determinates of NTD risk.
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Beaudin
authors.forename: Elena V
authors.initials: EV
authors.lastname: Abarinov
authors.forename: Drew M
authors.initials: DM
authors.lastname: Noden
authors.forename: Cheryll A
authors.initials: CA
authors.lastname: Perry
authors.forename: Stephanie
authors.initials: S
authors.lastname: Chu
authors.forename: Sally P
authors.initials: SP
authors.lastname: Stabler
authors.forename: Robert H
authors.initials: RH
authors.lastname: Allen
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Stover
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D002794:Choline / Q000494:pharmacology; D002796:Choline Deficiency / Q000150:complications; D004195:Disease Models, Animal; D005492:Folic Acid / Q000494:pharmacology*; D005494:Folic Acid Deficiency / Q000150:complications*; D015870:Gene Expression; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009436:Neural Tube Defects / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D011687:Purines / Q000096:biosynthesis; D012720:Severity of Illness Index; D013938:Thymidine Monophosphate / Q000096:biosynthesis*; D013940:Thymidylate Synthase / Q000378:metabolism; D014803:Vitamin B Complex / Q000494:pharmacology*
chemical_list: D015415:Biomarkers; D011687:Purines; D014803:Vitamin B Complex; D013938:Thymidine Monophosphate; D005492:Folic Acid; D013940:Thymidylate Synthase; D012696:Glycine Hydroxymethyltransferase; D002794:Choline; C030985:purine