Low folate induces abnormal neuronal maturation and DNA hypomethylation of neuronal differentiation-related genes in cultured mouse neural stem and progenitor cells

Abstract

Folate deficiency in a fetus is well known to cause neurodevelopment defects and development disorders. A low level of folate is also thought to be a risk for depression in adults. We have previously shown that post-weaning low folate induces neuronal immaturity in the dentate gyrus in mice, which suggests that low folate causes neuropsychological disorders via inhibition of neuronal maturation. In this study, we examined the effects of low folate on expression and epigenetic modification of genes involved in neuronal differentiation and maturation in primary mouse neural stem/progenitor cells (NSPCs) in vitro . An increase in Nestin (NSPC marker)-positive cells was observed in cells differentiated in a low folate medium for 3 days. An increase in βIII-tubulin (Tuj1: immature neuron marker)-positive cells and a decrease in microtubule-associated protein 2 (MAP2: mature neuron marker)-positive cells were observed in cells differentiated in a low folate medium for 7 days. In these cells, mRNA levels for genes involved in neuronal differentiation and maturation were altered. Hypomethylation of DNA, but not of histone proteins, was also observed at some promoters of these neuronal genes. The level of S -adenosylmethionine (SAM), a methyl donor, was decreased in these cells. The abnormalities in neural maturation and changes in gene expression in culture under low folate conditions were partially normalized by addition of SAM (5 μM). Based on these results, decreased SAM may induce DNA hypomethylation at genes involved in neuronal differentiation and maturation under low folate conditions, and this hypomethylation may be associated with low folate-induced neuronal immaturity.

Ischemic myelomalacia and closed spinal dysraphism in multiple finishing swine

“…Although there was strong evidence demonstrating a genetic component in the etiology, it was still challenged by numerous candidate genes, each individually insufficient to disrupt the embryogenesis of the neural tube. 6,11 Conversely, the accumulation of recessive mutations in some genes, such as those related to folate metabolism, 1 could be enhanced through inbreeding and predisposed to congenital malformations as observed in our case series.…”

Folate depletion alters mouse trophoblast stem cell regulationin vitro

“…Therefore, TSCs could self-renew and maintain stem cell identity in FD conditions, but this capability lessened over time in association with ectopic differentiation. We hypothesise that folate depletion disrupts DNA [20] and/or RNA [21] methylation maintenance at trophoblast stem cell regulator genes, thus altering pre- and post-transcriptional regulation.…”

Methods used to achieve different levels of the neuronal differentiation process in SH‐SY5Y and Neuro2a cell lines: An integrative review

“…Following a stimulus, the expression of some cytoskeleton active proteins that drive microtubules and their reorganization induces the production of neurites, which initiates the change in cell morphology. Class III‐tubulin (Tuj‐1), for example, is a protein that contributes to the formation of cytoskeletal microtubules and correlates with the early stages of neurite differentiation as shown in Figure 1 (Araki et al, 2021; Janke & Magiera, 2020; Mahabadi & Taghibiglou, 2020).…”

“…Neuronal differentiation is a multiphasic process that involves the expression of neuronal marker proteins at each stage, allowing the transition from immature to mature neurons to be distinguished (Araki et al, 2021; El Ayachi et al, 2018). Among the best known neuronal marker proteins are synaptophysin, synapsin, postsynaptic density protein (PSD95), synapse‐associated protein 97 (SAP97), synaptic vesicle protein 2 (SV2), neurofilaments (NF), neuron‐specific enolase (NSE), and Tuj‐1 and MAP2 (El Ayachi et al, 2018; Mahabadi & Taghibiglou, 2020).…”