Shmt1 and De Novo Thymidylate Biosynthesis Underlie Folate-responsive Neural Tube Defects in Mice

Overview

Journal Am J Clin Nutr

Publisher Elsevier

Specialty Nutritional Sciences

Date 2011 Feb 25

PMID 21346092

Citations 59

Authors

Anna E Beaudin

Elena V Abarinov

Drew M Noden

Cheryll A Perry

Stephanie Chu

Sally P Stabler

Robert H Allen

Patrick J Stover

Affiliations

Soon will be listed here.

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.

Objectives: 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.

Design: 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.

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References

Martinez Barbera J, Rodriguez T, Greene N, Weninger W, Simeone A, Copp A . Folic acid prevents exencephaly in Cited2 deficient mice. Hum Mol Genet. 2002; 11(3):283-93. DOI: 10.1093/hmg/11.3.283. View

Liu X, Szebenyi D, Anguera M, Thiel D, Stover P . Lack of catalytic activity of a murine mRNA cytoplasmic serine hydroxymethyltransferase splice variant: evidence against alternative splicing as a regulatory mechanism. Biochemistry. 2001; 40(16):4932-9. DOI: 10.1021/bi002598t. View

Woeller C, Anderson D, Szebenyi D, Stover P . Evidence for small ubiquitin-like modifier-dependent nuclear import of the thymidylate biosynthesis pathway. J Biol Chem. 2007; 282(24):17623-31. DOI: 10.1074/jbc.M702526200. View

Fleming A, Copp A . Embryonic folate metabolism and mouse neural tube defects. Science. 1998; 280(5372):2107-9. DOI: 10.1126/science.280.5372.2107. View

Field M, Szebenyi D, Stover P . Regulation of de novo purine biosynthesis by methenyltetrahydrofolate synthetase in neuroblastoma. J Biol Chem. 2005; 281(7):4215-21. DOI: 10.1074/jbc.M510624200. View

Anderson D, Woeller C, Stover P . Small ubiquitin-like modifier-1 (SUMO-1) modification of thymidylate synthase and dihydrofolate reductase. Clin Chem Lab Med. 2007; 45(12):1760-3. DOI: 10.1515/CCLM.2007.355. View

Blount B, Mack M, Wehr C, MacGregor J, Hiatt R, Wang G . Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci U S A. 1997; 94(7):3290-5. PMC: 20362. DOI: 10.1073/pnas.94.7.3290. View

Lu W, Zhu H, Wen S, Laurent C, Shaw G, Lammer E . Screening for novel PAX3 polymorphisms and risks of spina bifida. Birth Defects Res A Clin Mol Teratol. 2006; 79(1):45-9. PMC: 6532638. DOI: 10.1002/bdra.20322. View

Stabler S, Lindenbaum J, Savage D, Allen R . Elevation of serum cystathionine levels in patients with cobalamin and folate deficiency. Blood. 1993; 81(12):3404-13. View

10.

Herrera E, Samper E, Blasco M . Telomere shortening in mTR-/- embryos is associated with failure to close the neural tube. EMBO J. 1999; 18(5):1172-81. PMC: 1171208. DOI: 10.1093/emboj/18.5.1172. View

11.

Relton C, Wilding C, Laffling A, Jonas P, Burgess T, Binks K . Low erythrocyte folate status and polymorphic variation in folate-related genes are associated with risk of neural tube defect pregnancy. Mol Genet Metab. 2004; 81(4):273-81. DOI: 10.1016/j.ymgme.2003.12.010. View

12.

Wlodarczyk B, Tang L, Triplett A, Aleman F, Finnell R . Spontaneous neural tube defects in splotch mice supplemented with selected micronutrients. Toxicol Appl Pharmacol. 2005; 213(1):55-63. DOI: 10.1016/j.taap.2005.09.008. View

13.

McClive P, Sinclair A . Rapid DNA extraction and PCR-sexing of mouse embryos. Mol Reprod Dev. 2001; 60(2):225-6. DOI: 10.1002/mrd.1081. View

14.

Kirke P, Molloy A, Daly L, Burke H, Weir D, Scott J . Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects. Q J Med. 1993; 86(11):703-8. View

15.

Nikiforov M, Chandriani S, OConnell B, Petrenko O, Kotenko I, Beavis A . A functional screen for Myc-responsive genes reveals serine hydroxymethyltransferase, a major source of the one-carbon unit for cell metabolism. Mol Cell Biol. 2002; 22(16):5793-800. PMC: 133987. DOI: 10.1128/MCB.22.16.5793-5800.2002. View

16.

Carter M, Ulrich S, Oofuji Y, Williams D, Ross M . Crooked tail (Cd) models human folate-responsive neural tube defects. Hum Mol Genet. 1999; 8(12):2199-204. DOI: 10.1093/hmg/8.12.2199. View

17.

Anderson D, Stover P . SHMT1 and SHMT2 are functionally redundant in nuclear de novo thymidylate biosynthesis. PLoS One. 2009; 4(6):e5839. PMC: 2688753. DOI: 10.1371/journal.pone.0005839. View

18.

Harris M, Juriloff D . Mouse mutants with neural tube closure defects and their role in understanding human neural tube defects. Birth Defects Res A Clin Mol Teratol. 2006; 79(3):187-210. DOI: 10.1002/bdra.20333. View

19.

Czeizel A, Dudas I . Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med. 1992; 327(26):1832-5. DOI: 10.1056/NEJM199212243272602. View

20.

Christensen B, Arbour L, Tran P, Leclerc D, Sabbaghian N, Platt R . Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects. Am J Med Genet. 1999; 84(2):151-7. DOI: 10.1002/(sici)1096-8628(19990521)84:2<151::aid-ajmg12>3.0.co;2-t. View