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

Abstract

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.

Expression profiling of N6-methyladenosine-modified mRNA in PC12 cells in response to unconjugated bilirubin

“…Speci c differential expression of METTL13 and FTO and differential m 6 A methylation in different brain regions (medial prefrontal cortex and basolateral and central amygdala) were observed in mice during a stress response, which was consistent with the expression of glucocorticoids [29]. ALKBH5 overexpression inhibits cell proliferation via the Wnt/β-catenin signaling pathway, and METTL3 downregulation also reduces cell proliferation and increases apoptosis by inhibiting the Wnt/β-catenin signaling pathway [30]. METTL14 knockdown signi cantly reduced proliferation and promoted the differentiation of mouse embryonic neural stem cells, thereby inhibiting their self-renewal ability [31].…”

Identifying key m6A-methylated lncRNAs and genes associated with neural tube defects via integrative MeRIP and RNA sequencing analyses

“…The METTL3 -mediated m 6 A modification is essential for mammalian embryonic development ( Sui et al, 2020 ). A previous study has revealed that levels of m 6 A modification and METTL3 expression are lower in ethionine-induced NTD than in controls ( Zhang L. et al, 2021 ). Consistent with these findings, we found that the retinoic acid-induced NTD mouse model had dramatically decreased overall m 6 A levels and METTL3 expression levels than those in control mice.…”

Melatonin alleviates valproic acid-induced neural tube defects by modulating Src/PI3K/ERK signaling and oxidative stress

“…It has been proposed that the intricate orchestration of neural stem cell processes including proliferation, migration, differentiation, and apoptosis is a key determinant in neural tube formation [50] . Studies have substantiated that neural tube disorders can arise from diminished proliferation and heightened apoptosis of neuroepithelial cells within the developing neural tube [ 51 , 52 ]. VPA exposure has been linked to fetal neural tube DNA damage and leads to downstream alterations, including cell cycle arrest and apoptosis [53] .…”