Effects of methionine on the cytoplasmic distribution of actin and tubulin during neural tube closure in rat embryos

Moephuli, Shadrack R.; Klein, Norman W.; Baldwin, Michael; Krider, Hallie M.

doi:10.1073/pnas.94.2.543

Cited by 49 publications

(30 citation statements)

References 39 publications

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“…Protein methylation is also involved in neural tube development, and hypomethylation of neural tube proteins is accompanied by a failure of the neural tube to close in rat embryos cultured in methionine-deficient conditions (34). The cytoskeletal proteins β-actin and tubulin are known to be methylated during neural tube closure (35), and proper function of the cytoskeleton is required for cranial neural tube closure (reviewed in ref. 36).…”

Section: Discussionmentioning

confidence: 99%

Deletion of Mthfd1l causes embryonic lethality and neural tube and craniofacial defects in mice

Momb¹,

Lewandowski

Bryant³

et al. 2012

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

138

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Maternal supplementation with folic acid is known to reduce the incidence of neural tube defects (NTDs) by as much as 70%. Despite the strong clinical link between folate and NTDs, the biochemical mechanisms through which folic acid acts during neural tube development remain undefined. The Mthfd1l gene encodes a mitochondrial monofunctional 10-formyl-tetrahydrofolate synthetase, termed MTHFD1L. This gene is expressed in adults and at all stages of mammalian embryogenesis with localized regions of higher expression along the neural tube, developing brain, craniofacial structures, limb buds, and tail bud. In both embryos and adults, MTHFD1L catalyzes the last step in the flow of one-carbon units from mitochondria to cytoplasm, producing formate from 10-formyl-THF. To investigate the role of mitochondrial formate production during embryonic development, we have analyzed Mthfd1l knockout mice. All embryos lacking Mthfd1l exhibit aberrant neural tube closure including craniorachischisis and exencephaly and/or a wavy neural tube. This fully penetrant folate-pathway mouse model does not require feeding a folate-deficient diet to cause this phenotype. Maternal supplementation with sodium formate decreases the incidence of NTDs and partially rescues the growth defect in embryos lacking Mthfd1l . These results reveal the critical role of mitochondrially derived formate in mammalian development, providing a mechanistic link between folic acid and NTDs. In light of previous studies linking a common splice variant in the human MTHFD1L gene with increased risk for NTDs, this mouse model provides a powerful system to help elucidate the specific metabolic mechanisms that underlie folate-associated birth defects, including NTDs.

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Section: Discussionmentioning

confidence: 99%

Deletion of Mthfd1l causes embryonic lethality and neural tube and craniofacial defects in mice

Momb¹,

Lewandowski

Bryant³

et al. 2012

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

138

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show abstract

“…Failures of differentiation may occur because malfunctioning cytoskeletal elements cannot propagate the contraction wave. These cytoskeleton malfunctions could be due to the reduced level of posttranslational methylation in apical cytoskeleton that has been observed in rat embryos with NTDs (Moephuli, et al, 1997). In the embryo affected by an NTD, this particular failure is confined to embryonic neural tissue.…”

Section: Nuclear State Splitter and Ntdsmentioning

confidence: 99%

“…This residue is actively methylated by SAM during neural tube closure. Reduced methylation results in failure of these cytoskeletal elements to localize in the basal and apical ends of the cells (Moephuli, et al, 1997). Failure of appropriate localization of the cytoskeletal elements of neural tissue would result in mechanical failures of cell contractions and movements and thereby cause NTDs.…”

Section: Polyunsaturated Fatty Acid Synthesis May Contribute To Ntdsmentioning

confidence: 99%

A hypothesis linking low folate intake to neural tube defects due to failure of post-translation methylations of the cytoskeleton

Björklund¹,

Gordon²

2006

Int. J. Dev. Biol.

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Neural tube defects are serious congenital malformations which can be prevented by periconceptional folic acid supplementation. We hypothesize that folic acid provides the methyl group used for post-translational methylation of arginine and histidine in the highly conserved regulatory domains of the cytoskeleton and that these are required for neural tissue differentiation. Presumptive neural tissue has an unusually high need for folates due to the activity of phosphoethanolamine methyl transferase in producing neural tissue specific lipids at a time when the cytoskeleton is also competing for methylation. According to the cell state splitter hypothesis, the cytoskeleton is required to coordinate the spatial and temporal component of differentiation. When folate supply is low and the cytoskeleton is not methylated properly, the result is a neural tube defect due to failure of this coordination.

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“…Elevated levels of Hcy, as an intermediate in the methylation cycle, might interfere with methylation of proteins or genes. Data from rat embryo studies suggest that the methylation of actin and tubulin is required for proper neural tube closure (Moephuli et al 1997). Whether Hcy exerts its effect through direct methylation of actin, through methylation of actin-related proteins or genes or through an alternative mechanism remains to be determined.…”

Section: Anterior Cell Movements Contribute To the Anterior Neural Platementioning

confidence: 99%

Morphogenetic movements during cranial neural tube closure in the chick embryo and the effect of homocysteine

et al. 2005

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In order to unravel morphogenetic mechanisms involved in neural tube closure, critical cell movements that are fundamental to remodelling of the cranial neural tube in the chick embryo were studied in vitro by quantitative time-lapse video microscopy. Two main directions of movements were observed. The earliest was directed medially; these cells invaginated into a median groove and were the main contributors to the initial neural tube closure. Once the median groove was completed, cells changed direction and moved anteriorly to contribute to the anterior neural plate and head fold. This plate developed into the anterior neuropore, which started to close from the 4-somite stage onwards by convergence of its neural folds. Posteriorly, from the initial closure site onwards, the posterior neuropore started to close almost instantaneously by convergence of its neural folds. Homocysteine is adversely involved in human neural tube closure defects. After application of a single dose of homocysteine to chick embryos, a closure delay at the initial closure site and at the neuropores, flattening of the head fold and neural tube, and a halt of cell movements was seen. A possible interference of Hcy with actin microfilaments is discussed.

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Effects of methionine on the cytoplasmic distribution of actin and tubulin during neural tube closure in rat embryos

Cited by 49 publications

References 39 publications

Deletion of Mthfd1l causes embryonic lethality and neural tube and craniofacial defects in mice

Deletion of Mthfd1l causes embryonic lethality and neural tube and craniofacial defects in mice

A hypothesis linking low folate intake to neural tube defects due to failure of post-translation methylations of the cytoskeleton

Morphogenetic movements during cranial neural tube closure in the chick embryo and the effect of homocysteine

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