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

Kit-Yi Leung,Yun Jin Pai,Qiuying Chen,Chloe Santos,Enrica Calvani,Sonia Sudiwala,Dawn Savery,Markus Ralser,Steven S Gross,Andrew J Copp,Nicholas D.E Greene

doi:10.1016/j.celrep.2017.10.072

Kit-Yi Leung, Yun Jin Pai + Show 9 more

Open Access

https://doi.org/10.1016/j.celrep.2017.10.072

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Abstract

SummaryAbnormal 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.

Highlights

Folate one-carbon metabolism (FOCM) comprises an interlinked network of reactions that transfer one-carbon (1C) units for numerous cellular functions (Figure 1A; Tibbetts and Appling, 2010; Locasale, 2013)
Among litters of embryos generated by intercrossing of Mthfr+/À mice, homozygous null embryos were present in the expected Mendelian ratio, and neural tube defects (NTDs) were not observed (n = 46 MthfrÀ/À examined at embryonic day 9.5 [E9.5]–E12.5; Table S1), consistent with previous findings (Chen et al, 2001; De Castro et al, 2010)
The major folate present in plasma is 5-methyl THF, and it is proposed that folate obtained from the maternal circulation may sustain MthfrÀ/À embryos in utero, facilitating neural tube closure and allowing survival to birth (Schwahn et al, 2004)

Summary

Introduction

Folate one-carbon metabolism (FOCM) comprises an interlinked network of reactions that transfer one-carbon (1C) units for numerous cellular functions (Figure 1A; Tibbetts and Appling, 2010; Locasale, 2013). The association of folate status with birth defects, such as neural tube defects (NTDs), implicates FOCM in playing a key role during development. Flux through FOCM depends on both the availability of tetrahydrofolate (THF), which is the 1C ‘‘carrier’’ in the folate cycle, and on supply of 1C units, principally derived from serine (Davis et al, 2004; Ducker and Rabinowitz, 2017; Yang and Vousden, 2016). Maternal folate deficiency exacerbates NTDs in some genetically susceptible mouse strains (Burren et al, 2008, 2010; Beaudin et al, 2011)

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