Development of head organizer of the mouse embryo depends on a high level of mitochondrial metabolism

Zhou, Xin; Anderson, Kathryn V.

doi:10.1016/j.ydbio.2010.04.031

Cited by 14 publications

(15 citation statements)

References 61 publications

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“…1), significantly improves neurulation in Amt null embryos, whereas folic acid has no effect (20). The importance of the GCS to neural tube development is also supported by the occurrence of NTDs in the nehe mouse (21). The nehe mouse carries a hypomorphic allele of lipoic acid synthetase, the mitochondrial enzyme that catalyzes the synthesis of lipoic acid, an essential cofactor for GCS and several other mitochondrial enzymes.…”

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.

136

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.

136

138

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“…In addition to ATP sensing, AMPK also has a role in suppressing lipid synthesis and stimulating mitochondrial uptake and oxidation of fatty acids [Yuan et al, 2013]. The importance of mitochon-drial metabolism for cranial development is highlighted by the phenotype of the ENU-induced mutant nearly headless, nehe [Zhou and Anderson, 2010]. In these mutants, the gene encoding the enzyme catalyzing synthesis of Lipoic acid ( Lias ) is disrupted.…”

Section: Mechanisms and Mouse Models: Nutrient Modulation Of Neural Tmentioning

confidence: 99%

“…Since upregulation of AMPK can inhibit the cell cycle, the mutants exhibit reduced cell proliferation, which would account for their smaller size, but not the cranially restricted phenotype. Interestingly, cellular morphology was perturbed in the anterior visceral endo-derm and the primitive streak [Zhou and Anderson, 2010], leading the authors to hypothesize that the pre-chordal plate has a particularly high requirement for mitochondrial metabolism. Another line of evidence for the role of mitochondria comes from the high penetrance of exencephaly and craniorachischisis in mutants with deficiency of mitochondrial MTHFD1like [Momb et al, 2013].…”

Section: Mechanisms and Mouse Models: Nutrient Modulation Of Neural Tmentioning

confidence: 99%

Modeling anterior development in mice: Diet as modulator of risk for neural tube defects

Kappen¹

2013

American J of Med Genetics Pt C

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Head morphogenesis is a complex process that is controlled by multiple signaling centers. The most common defects of cranial development are craniofacial defects, such as cleft lip and cleft palate, and neural tube defects, such as anencephaly and encephalocoele in humans. More than 400 genes that contribute to proper neural tube closure have been identified in experimental animals, but only very few causative gene mutations have been identified in humans, supporting the notion that environmental influences are critical. The intrauterine environment is influenced by maternal nutrition, and hence, maternal diet can modulate the risk for cranial and neural tube defects. This article reviews recent progress toward a better understanding of nutrients during pregnancy, with particular focus on mouse models for defective neural tube closure. At least four major patterns of nutrient responses are apparent, suggesting that multiple pathways are involved in the response, and likely in the underlying pathogenesis of the defects. Folic acid has been the most widely studied nutrient, and the diverse responses of the mouse models to folic acid supplementation indicate that folic acid is not universally beneficial, but that the effect is dependent on genetic configuration. If this is the case for other nutrients as well, efforts to prevent neural tube defects with nutritional supplementation may need to become more specifically targeted than previously appreciated. Mouse models are indispensable for a better understanding of nutrient–gene interactions in normal pregnancies, as well as in those affected by metabolic diseases, such as diabetes and obesity.

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“…2001; Yu et al. 2010) and preimplantation embryo development (Zhou and Anderson 2010; Sansinena et al. 2010).…”

Section: Introductionmentioning

confidence: 99%

“…Mitochondria in competent embryos showed intermediate levels of activity higher than that in non-competent embryos and lower than that in the blastocyst stage (Tarazona et al 2006). The amount of mitochondria and their translocation may also associate with oocyte maturation (Krisher and Bavister 1998;Stojkovic et al 2001;Yu et al 2010) and preimplantation embryo development (Zhou and Anderson 2010;Sansinena et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Translocation of Active Mitochondria During Buffalo (Bubalus bubalis) Oocytes In vitro Maturation, Fertilization and Preimplantation Embryo Development

Huang

et al. 2011

Reprod Domestic Animals

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Mitochondria are energy-supplying organelles, whose distribution and functional integrity are necessary for cell survival and development. In this study, the mitochondrial distribution pattern and activity during buffalo oocyte in vitro maturation, fertilization and preimplantation embryo development were revealed using a fluorescent dye and confocal laser scanning microscopy. Distribution of active mitochondria changed during buffalo oocyte in vitro maturation. Active mitochondria were transferred from the outer to inner and perinuclear cytoplasm as oocytes matured in vitro and aggregated around the pronuclei in the fertilized eggs. Active mitochondria were also observed in preimplantation embryos. In the two-cell stage, they were distributed throughout the cytoplasm. From four-cell to the spherical embryonic stages, active mitochondria translocated to the perinuclear and the periphery of the cytoplasm. These results confirm that mitochondria play an important role in oocyte and embryo. The distribution of active mitochondria might be a marked feature of buffalo oocyte maturation, fertilization and preimplantation embryo development in vitro.

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Development of head organizer of the mouse embryo depends on a high level of mitochondrial metabolism

Cited by 14 publications

References 61 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

Modeling anterior development in mice: Diet as modulator of risk for neural tube defects

Translocation of Active Mitochondria During Buffalo (Bubalus bubalis) Oocytes In vitro Maturation, Fertilization and Preimplantation Embryo Development

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