Excess methionine suppresses the methylation cycle and inhibits neural tube closure in mouse embryos

Dunlevy, Louisa P. E.; Burren, Katie A.; Chitty, Lyn S.; Copp, Andrew J.; Greene, Nicholas D. E.

doi:10.1016/j.febslet.2006.04.020

Cited by 48 publications

(35 citation statements)

References 26 publications

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“…Recent examination of this hypothesis by Dunlevy et al (2006aDunlevy et al ( , 2006b) has provided preliminary support for a direct role of methionine and methionine-dependent cellular methylation in neural tube closure. In two separate studies, the authors demonstrated that culture of neurulation-stage mouse embryos with excess methionine or inhibitors of methionine adenosyl transferase (MAT) resulted in an exencephalic phenotype at high frequency.…”

Section: Alteration In Methylation Cycle and Ntdsmentioning

confidence: 92%

Folate‐mediated one‐carbon metabolism and neural tube defects: Balancing genome synthesis and gene expression

Beaudin

Stover

2007

Birth Defects Research Pt C

125

117

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Neural tube defects (NTDs) refer to a cluster of neurodevelopmental conditions associated with failure of neural tube closure during embryonic development. Worldwide prevalence of NTDs ranges from approximately 0.5 to 60 per 10,000 births, with regional and population-specific variation in prevalence. Numerous environmental and genetic influences contribute to NTD etiology; accumulating evidence from population-based studies has demonstrated that folate status is a significant determinant of NTD risk. Folate-mediated one-carbon metabolism (OCM) is essential for de novo nucleotide biosynthesis, methionine biosynthesis, and cellular methylation reactions. Periconceptional maternal supplementation with folic acid can prevent occurrence of NTDs in the general population by up to 70%; currently several countries fortify their food supply with folic acid for the prevention of NTDs. Despite the unambiguous impact of folate status on NTD risk, the mechanism by which folic acid protects against NTDs remains unknown. Identification of the mechanism by which folate status affects neural tube closure will assist in developing more efficacious and better targeted preventative measures. In this review, we summarize current research on the relationship between folate status and NTDs, with an emphasis on linking genetic variation, folate nutriture, and specific metabolic and/or genomic pathways that intersect to determine NTD outcomes.

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Section: Alteration In Methylation Cycle and Ntdsmentioning

confidence: 92%

Folate‐mediated one‐carbon metabolism and neural tube defects: Balancing genome synthesis and gene expression

Beaudin

Stover

2007

Birth Defects Research Pt C

125

117

View full text Add to dashboard Cite

show abstract

“…Exposure of non-mutant embryos to excess methionine in embryo culture can also cause cranial NTDs associated with suppression of the methylation cycle (Dunlevy et al, 2006a). Thus, the effect of methionine on heterozygous Sp 2H /1 embryos may reflect the underlying susceptibility of these embryos to develop NTDs, as opposed to a specific interaction of methionine with the splotch defect.…”

Section: Interaction Of the Splotch Mutation With Environmental Factomentioning

confidence: 97%

Understanding the causes and prevention of neural tube defects: Insights from the splotch mouse model

Greene¹,

Massa²,

Copp³

2009

Birth Defects Research

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Splotch mutant mice develop neural tube defects (NTDs), comprising exencephaly and/or spina bifida, as well as neural crest-related defects and abnormalities of limb musculature. Defects in splotch mice result from mutations in Pax3, and some human NTDs may also result from mutations in the human PAX3 gene. Pax3 encodes a transcription factor whose function may influence expression of multiple downstream genes associated with a variety of cellular properties (including apoptosis, adhesion, proliferation, and differentiation), that could be important for neural tube closure. The frequency of NTDs varies between mutant alleles and is also influenced by genetic background and environmental factors. Notably, splotch provides a model for folic acid-preventable NTDs, and conversely, dietary folate deficiency exacerbates NTDs. Understanding the molecular and cellular basis of splotch NTDs, as well as the mechanisms by which the frequency of defects is influenced by genetic and environmental factors (such as sub-optimal folate status), may provide insight into the causation of these severe congenital malformations in humans.

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“…Embryos were explanted and cultured in rat serum as described previously (15). Yolk sac circulation, crown-rump length, and somite number provided measures of viability, growth, and developmental progression, respectively (31). Stock solutions of z-VAD-fmk (Sigma-Aldrich) in DMSO and pifithrin-␣ (Calbiochem) in PBS were added to cultures as 0.1% (vol/vol) additions to obtain the final concentrations of 200 M and 500 M, respectively.…”

Section: Methodsmentioning

confidence: 99%

Apoptosis is not required for mammalian neural tube closure

Massa

Savery

Ybot‐González

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Apoptotic cell death occurs in many tissues during embryonic development and appears to be essential for processes including digit formation and cardiac outflow tract remodeling. Studies in the chick suggest a requirement for apoptosis during neurulation, because inhibition of caspase activity was found to prevent neural tube closure. In mice, excessive apoptosis occurs in association with failure of neural tube closure in several genetic mutants, but whether regulated apoptosis is also necessary for neural tube closure in mammals is unknown. Here we investigate the possible role of apoptotic cell death during mouse neural tube closure. We confirm the presence of apoptosis in the neural tube before and during closure, and identify a correlation with 3 main events: bending and fusion of the neural folds, postfusion remodeling of the dorsal neural tube and surface ectoderm, and emigration of neural crest cells. Both Casp3 and Apaf1 null embryos exhibit severely reduced apoptosis, yet neurulation proceeds normally in the forebrain and spine. In contrast, the mutant embryos fail to complete neural tube closure in the midbrain and hindbrain. Application of the apoptosis inhibitors z-Vad-fmk and pifithrin-␣ to neurulation-stage embryos in culture suppresses apoptosis but does not prevent initiation or progression of neural tube closure along the entire neuraxis, including the midbrain and hindbrain. Remodeling of the surface ectoderm to cover the closed tube, as well as delamination and migration of neural crest cells, also appear to be normal in the apoptosis-suppressed embryos. We conclude that apoptosis is not required for neural tube closure in the mouse embryo.cell death ͉ embryo ͉ morphogenesis ͉ neurulation

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Excess methionine suppresses the methylation cycle and inhibits neural tube closure in mouse embryos

Cited by 48 publications

References 26 publications

Folate‐mediated one‐carbon metabolism and neural tube defects: Balancing genome synthesis and gene expression

Folate‐mediated one‐carbon metabolism and neural tube defects: Balancing genome synthesis and gene expression

Understanding the causes and prevention of neural tube defects: Insights from the splotch mouse model

Apoptosis is not required for mammalian neural tube closure

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