Cell Rep. 2017 Nov 14;21(7):1795-1808. doi: 10.1016/j.celrep.2017.10.072.

Partitioning of One-Carbon Units in Folate and Methionine Metabolism Is Essential for Neural Tube Closure.

Leung KY¹, Pai YJ¹, Chen Q², Santos C¹, Calvani E³, Sudiwala S¹, Savery D¹, Ralser M³, Gross SS², Copp AJ¹, Greene NDE⁴.

Author information

1: Developmental Biology & Cancer Programme, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
2: Department of Pharmacology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
3: The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
4: Developmental Biology & Cancer Programme, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK. Electronic address: n.greene@ucl.ac.uk.

Abstract

Abnormal folate one-carbon metabolism (FOCM) is implicated in neural tube defects (NTDs), severe malformations of the nervous system. MTHFR mediates unidirectional transfer of methyl groups from the folate cycle to the methionine cycle and, therefore, represents a key nexus in partitioning one-carbon units between FOCM functional outputs. Methionine cycle inhibitors prevent neural tube closure in mouse embryos. Similarly, the inability to use glycine as a one-carbon donor to the folate cycle causes NTDs in glycine decarboxylase (Gldc)-deficient embryos. However, analysis of Mthfr-null mouse embryos shows that neither S-adenosylmethionine abundance nor neural tube closure depend on one-carbon units derived from embryonic or maternal folate cycles. Mthfr deletion or methionine treatment prevents NTDs in Gldc-null embryos by retention of one-carbon units within the folate cycle. Overall, neural tube closure depends on the activity of both the methionine and folate cycles, but transfer of one-carbon units between the cycles is not necessary.