Neural tube defects (NTDs) are complex congenital malformations resulting from failure of neural tube closure during embryogenesis, which is affected by the interaction of genetic and environmental factors. It is well known that folate deficiency increases the incidence of NTDs; however, the underlying mechanism remains unclear. Folate deficiency not only causes DNA hypomethylation, but also blocks the synthesis of 2′-deoxythymidine-5′–monophosphate (dTMP) and increases uracil misincorporation, resulting in genomic instabilities such as base mismatch, DNA breakage, and even chromosome aberration. DNA repair pathways are essential for ensuring normal DNA synthesis, genomic stability and integrity during embryonic neural development. Genomic instability or lack of DNA repair has been implicated in risk of development of NTDs. Here, we reviewed the relationship between folate deficiency, DNA repair pathways and NTDs so as to reveal the role and significance of DNA repair system in the pathogenesis of NTDs and better understand the pathogenesis of NTDs.

X-inactive specific transcript (Xist) is a main regulator of X chromosome inactivation in mammals, which silences most genes on X chromosome in a cis way. Xist is a kind of lncRNA, which cannot encode the transcript of protein. In addition, Xist RNA mediates the X chromosome inactivation (XCI) process to achieve dose compensation between the sexes. Recent studies have identified that Xist RNA regulates gene expression by recruiting factors/complexes to modify potential chromatin, which were involved in diseases such as neuroinflammation, autoimmune diseases and cancers. In this paper, the research progress of Xist RNA causing a series of diseases in mammalian cells is reviewed, which makes it a potential target for treating human diseases and provides a new direction for further study of diseases.

Neural-tube defects (NTDs) are one type of the most serious birth defects. Studies have shown that inositol deficiency is closely related to the occurrence of NTDs. Bone morphogenetic protein (BMP)-mediated Smad signaling pathways have been implicated in neurogenesis and neural-tube closure. However, the role of the BMP/Smad pathway in inositol-deficiency-induced NTDs remains unclear. Inositol-deficiency models in C57 mice and mouse neural stem cells (mNSCs) were induced with Li₂CO₃ treatment or inositol withdrawal. The role of the BMP/Smad pathway in the regulation of cell proliferation and the development of NTDs was determined utilizing qRT-PCR, HE staining, Western blot, immunostaining, MTT assay, EdU staining, and flow cytometry. The intraperitoneal injection of Li₂CO₃ at Embryonic Day 7.5 induced the occurrence of NTDs. The mRNA levels of Bmp2, Bmp4, Smad1, Smad5, Smad8 and Runx2, the phosphorylation of Smad1/5/8, and the nuclear translocation of Runx2 were significantly increased in NTD embryonic brain tissues and mNSCs exposed to Li₂CO₃ or an inositol-free medium, which were suppressed by BMP receptor selective inhibitor LDN-193189. The Li₂CO₃-induced phosphorylation of Smad1/5/8 was inhibited by inositol supplementation. Cell proliferation was significantly promoted by Li₂CO₃ exposure or the absence of inositol in mNSCs, which was reversed by LDN-193189. These results suggest that the activation of the BMP/Smad signaling pathway might play an important role in the development of NTDs induced by maternal Li₂CO₃ exposure via inositol deficiency.

Lithium, which is widely used in medicine and batteries, has become increasingly prevalent in the environment, raising concerns about its impact on human health. Lithium carbonate (Li₂CO₃) is a common treatment and relapse prevention method for bipolar disorder. It can freely cross the placental barrier; however, lithium treatment is accompanied by side effects, particularly in women of reproductive age. Among these, neural tube defects (NTDs) have the most severe impact on nervous system development; however, their underlying mechanisms remain unclear. This study explored the potential mechanisms by which Li₂CO₃ exposure contributes to NTDs. Pregnant mice were intraperitoneally injected with Li₂CO₃ (360 mg/kg), which mimicked high-exposure scenarios such as an unintended pregnancy during lithium therapy or exposure to industrial contamination. Embryos were assessed for morphological changes, primary cilia length, and endoplasmic reticulum (ER) homeostasis using histological analysis, scanning electron microscopy, PCR array analysis, immunofluorescence, and quantitative real-time PCR. Network and bioinformatics analyses were used to identify primary molecular targets and pathways. We also evaluated the effects of inositol supplementation on cilia during Li₂CO₃ exposure. The results revealed that treatment with Li₂CO₃ at 360 mg/kg induced exencephaly in some embryos, reduced primary cilia length, and dysregulated cilia-associated gene expression in the neural tube. PCR Array, network metabolism, and immunofluorescence analyses revealed that HSP90AB1, a critical regulator of ER homeostasis, was upregulated in Li₂CO₃-treated embryos with NTDs. Li₂CO₃ exposure disturbed ER homeostasis in the developing brain. Interestingly, inositol supplementation partially rescued ciliogenesis impairment in lithium-treated NIH3T3 cells. Li₂CO₃ exposure disrupted primary ciliary development and ER homeostasis in the embryonic neural tube. Maintaining adequate maternal inositol levels during Li₂CO₃ exposure before and during pregnancy prevents NTDs. These findings help in better understanding and reassessing the risks associated with lithium, especially in terms of maternal and fetal health.