Aberrant Gcm1 expression mediates Wnt/β-catenin pathway activation in folate deficiency involved in neural tube defects

Li, Jianting; Xie, Qijun; Gao, Jun; Wang, Fang; Bao, Yihua; Wu, Lihua; Yang, Lihong; Liu, Zhizhen; Guo, Rui; Khan, Ajab; Liú, Dan; Li, Caihua; Wu, Jianxin; Xie, Jun

doi:10.1038/s41419-020-03313-z

Cited by 9 publications

(11 citation statements)

References 35 publications

(40 reference statements)

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“…On the contrary, the expression levels of β-catenin and TCF-4 protein were significantly decreased. These results were consistent with Li et al [ 4 ].…”

Section: Discussionsupporting

confidence: 94%

“…A recent study reported that m6A modification of FZD10 mRNA contributes to PARP inhibitors resistance in cells via upregulation of Wnt/β-catenin pathway [ 39 ]. The previous research group underwent low-folate culture and performed expression profiling, and they also found that the Wnt/β-catenin signaling pathway is involved in folic acid metabolism [ 4 ]. In our study, we found that ethionine inhibits the activation of the Wnt/β-catenin signaling pathway, leading to changes in the expression of classic proteins and downstream target genes, which is reflected as the expression of upstream classical protein Axin-2 was up-regulated.…”

Section: Discussionmentioning

confidence: 99%

“…The pathogenesis of NTDs involves both genetic and environmental factors. Many results suggest that folate deficiency is a risk factor for NTDs [ 2 – 4 ]. At present, folic acid has become a new treatment for NTDs, however, it cannot prevent all types of NTDs [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…Previous research has also found that folic acid supplementation protected against PM2.5 cardiac development toxicity by regulating Wnt/β-catenin signal pathways [ 28 ]. Our previous study finds that low folate promotes Wnt/β-catenin signaling by activating Gcm1, and ultimately lead to NTDs [ 4 ]. However, the regulatory mechanism by which the Wnt/β-catenin signaling pathway affects neural tube closure is unclear.…”

Section: Introductionmentioning

confidence: 99%

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Ethionine-mediated reduction of S-adenosylmethionine is responsible for the neural tube defects in the developing mouse embryo-mediated m6A modification and is involved in neural tube defects via modulating Wnt/β-catenin signaling pathway

Zhang

Cao

et al. 2021

Epigenetics & Chromatin

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Neural tube defects (NTDs) remain one of the most life-threatening birth defects affecting infants. Most patients with NTDs eventually develop lifelong disability, which cause significant morbidity and mortality and seriously reduce the quality of life. Our previous study has found that ethionine inhibits cell viability by disrupting the balance between proliferation and apoptosis, and preventing neural stem cells from differentiating into neurons and astrocytes. However, how ethionine participates in the pathogenesis of neural tube development through N6-methyladenosine (m6A) modification remains unknown. This study aims to investigate METTL3- and ALKBH5-mediated m6A modification function and mechanism in NTDs. Herein, our results demonstrate that SAM play not only a compensatory role, it also leads to changes of m6A modification in neural tube development and regulation. Additionally, these data implicate that METTL3 is enriched in HT-22 cells, and METTL3 knockdown reduces cell proliferation and increases apoptosis through suppressing Wnt/β-catenin signaling pathway. Significantly, overexpression of ALKBH5 can only inhibit cell proliferation, but cannot promote cell apoptosis. This research reveals an important role of SAM in development of NTDs, providing a good theoretical basis for further research on NTDs. This finding represents a novel epigenetic mechanism underlying that the m6A modification has profound and lasting implications for neural tube development.

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“…On the contrary, the expression levels of β-catenin and TCF-4 protein were significantly decreased. These results were consistent with Li et al [ 4 ].…”

Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ethionine-mediated reduction of S-adenosylmethionine is responsible for the neural tube defects in the developing mouse embryo-mediated m6A modification and is involved in neural tube defects via modulating Wnt/β-catenin signaling pathway

Zhang

Cao

et al. 2021

Epigenetics & Chromatin

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“…Wnt/β-catenin signaling pathway involved in embryonic neural development and neural tube closure, especially NTDs [18,19]. In our previous study, we have demonstrated the depleted SAM could lead to the occurrence of NTDs.…”

Section: Sam Regulates Cell Function Via Activating Wnt/β-catenin Signalingmentioning

confidence: 94%

Reduced H3K27me3 Suppresses Wnt/β-catenin Signaling by S-adenosylmethionine Deficiency in Neural Tube Development

Zhang

Wang

Cao

et al. 2021

Preprint

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Background: S-adenosylmethionine as a major methyl donor play a key role in methylation modification in vivo, and its disorder was closely related to neural tube defects. However, the underlying mechanism between SAM deficiency and NTDs remained unclear.Methods: we investigated the association between histone methylation modification and Wnt/β-catenin signaling pathway in NTDs induced by SAM deficiency. The levels of SAM and SAH were determined by enzyme linked immunosorbent assay. The expressions of H3K27me3 and Wnt/β-catenin signaling pathway specific markers were demonstrated by western blotting, reverse transcription, and quantitative PCR and immunofluorescence in ethionine induced E11.5 mouse NTDs and NSCs models. Results: we found that the incidence rate of NTDs induced by ethionine were 46.2%, post treatment of ethionine combined with SAM, the incidence rate of NTDs was reduced to 26.2%. The level of SAM was significantly decreased (P<0.05) and a reduction in the SAM/SAH ratio was observed. The SAM depletion caused the reduction of both H3K27me3 modifications and UTX activity, and inhibited the marker proteins (β-catenin, TCF-4, Axin-2, p-GSK-3β, CyclinD1, and C-myc) in Wnt/β-catenin signaling pathway (P<0.05). The differentiations of neural stem cells into neurons and oligodendrocytes were inhibited under SAM deficiency (P<0.05).Conclusions: These results indicated that the depletion of SAM led to reduced H3K27me3 modifications, prevented the activation of Wnt/β-catenin signaling pathway and NSCs differentiation, which provided an understanding of the novel function of epigenetic regulation in NTDs.

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Arsenic disturbs neural tube closure involving AMPK/PKB-mTORC1-mediated autophagy in mice

Li,

Cui

et al. 2024

Food and Chemical Toxicology

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Aberrant Gcm1 expression mediates Wnt/β-catenin pathway activation in folate deficiency involved in neural tube defects

Cited by 9 publications

References 35 publications

Ethionine-mediated reduction of S-adenosylmethionine is responsible for the neural tube defects in the developing mouse embryo-mediated m6A modification and is involved in neural tube defects via modulating Wnt/β-catenin signaling pathway

Ethionine-mediated reduction of S-adenosylmethionine is responsible for the neural tube defects in the developing mouse embryo-mediated m6A modification and is involved in neural tube defects via modulating Wnt/β-catenin signaling pathway

Reduced H3K27me3 Suppresses Wnt/β-catenin Signaling by S-adenosylmethionine Deficiency in Neural Tube Development

Arsenic disturbs neural tube closure involving AMPK/PKB-mTORC1-mediated autophagy in mice

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