The complex roles of m 6 A modifications in neural stem cell proliferation, differentiation, and self-renewal and implications for memory and neurodegenerative diseases

Abstract

N6-methyladenosine (m 6 A), the most prevalent and conserved RNA modification in eukaryotic cells, profoundly influences virtually all aspects of mRNA metabolism. mRNA plays crucial roles in neural stem cell genesis and neural regeneration, where it is highly concentrated and actively involved in these processes. Changes in m 6 A modification levels and the expression levels of related enzymatic proteins can lead to neurological dysfunction and contribute to the development of neurological diseases. Furthermore, the proliferation and differentiation of neural stem cells, as well as nerve regeneration, are intimately linked to memory function and neurodegenerative diseases. This paper presents a comprehensive review of the roles of m 6 A in neural stem cell proliferation, differentiation, and self-renewal, as well as its implications in memory and neurodegenerative diseases. m 6 A has demonstrated divergent effects on the proliferation and differentiation of neural stem cells. These observed contradictions may arise from the time-specific nature of m 6 A and its differential impact on neural stem cells across various stages of development. Similarly, the diverse effects of m 6 A on distinct types of memory could be attributed to the involvement of specific brain regions in memory formation and recall. Inconsistencies in m 6 A levels across different models of neurodegenerative disease, particularly Alzheimer's disease and Parkinson's disease, suggest that these disparities are linked to variations in the affected brain regions. Notably, the opposing changes in m 6 A levels observed in Parkinson's disease models exposed to manganese compared to normal Parkinson's disease models further underscore the complexity of m 6 A's role in neurodegenerative processes. The roles of m 6 A in neural stem cell proliferation, differentiation, and self-renewal, and its implications in memory and neurodegenerative diseases, appear contradictory. These inconsistencies may be attributed to the time-specific nature of m 6 A and its varying effects on distinct brain regions and in different environments.

Figure 1

Timeline depicting essential discoveries of m⁶A in the field of nervous system research. This timeline shows the important role of m⁶A in the nervous system. Created using Microsoft PowerPoint 2019. m⁶A: N6-methyladenosine.

Figure 2

Effects of m⁶A on NSCs during repair of injured nerve tissue. A, B, and C are related to proliferation and differentiation; D is associated with self-renewal. (A) ZFP217 and METTL14 compete to occupy METTL3 on mRNA. At the beginning of differentiation, binding of METTL14 to METTL3, instead of ZFP217 (shown by red arrow), is observed because of a decrease in ZFP217 (shown by gray arrow). Further m⁶A mRNAs that are formed can be degraded, ensuring NSC differentiation. FMRP and YTHDF2 specifically recognize RNA m⁶A modification. The former heightens mRNA stability, and the latter recruits endoribonuclease, degrading multiple mRNAs. Both sustain the normal proliferation and differentiation of NSCs. (B) A deficiency in FTO in NSCs leads to the elevated degradation of BDNF mRNAs due to excessive m⁶A modifications. This, in turn, results in reduced BDNF expression (indicated by a gray arrow) and a subsequent impairment of the BDNF/AKT signaling pathway. In Fto-deficient aNSCs, cell proliferation and differentiation are inhibited, which ultimately impairs learning and memory functions. (C) In Mettl3-defective mice, levels of m⁶A are reduced (indicated by a gray arrow) in the neurogenesis of aNSCs. This affects the morphological maturation of new neurons and impairs the differentiation of aNSCs toward the glial lineage. Knockout of Mettl14 in mouse embryo NSCs led to a decrease in the quantity of astrocytes (indicated by a gray arrow). In mice with nerve damage, the production of MBP caused a reduction in METTL3/14 expression and an increase in FTO/ALKBH5 expression, resulting in decreased m⁶A levels (indicated by a gray arrow). (D) When the level of m⁶A decreases (indicated by a gray arrow), the mRNA of HMRs becomes unstable. This instability leads to the activation of differentiation genes and the inhibition of proliferation genes. This consequently promotes NSC self-renewal and reduces NSC premature differentiation. Created using Microsoft PowerPoint 2019. Red plus sign (+): positive effect or promoted; red minus sign (−): negative effect or inhibited. Akt: Protein kinase B; ALKBH5: alkB homolog 5; aNSCs: Adult neural stem cells; BDNF: brain-derived neurotrophic factor; FMRP: fragile mental retardation protein; FTO: fat mass and obesity-associated; HMRs: histone modification regulators; MBP: myelin basic protein; METTL14: methyltransferase like-14; METTL3: methyltransferase like-3; NSCs: neural stem cells; YTHDF2: YT521-B homology domain-containing family protein 2; ZFP217: zinc finger protein 217.

Figure 3

Roles of m⁶A in inflammation induced by microglia. lGF2BP1 stabilizes mRNAs to heighten their expression (e.g., GBP11 and Cp mRNA) by mediating lipopolysaccharides (LPS), leading to pro-inflammatory cytokine production and further inflammation. lGF2BP1 also promotes the m⁶A modification of GBP11 and Cp mRNA to adjust microglia-induced inflammation. METTL3 promotes the expression of TRAF6 and NF-κB (inflammatory cytokine and protein). METTL3 levels are positively correlated with TRAF6 (shown by double-headed arrow), and the two can combine. Created using Microsoft PowerPoint 2019. Red plus sign (+): positive effect or promoted. Cp: Ceruloplasmin; GBP11: guanylate-binding protein 11; METTL3: methyltransferase like-3; NF-κB: nuclear factor kappa-B; TNF: tumor necrosis factor; TRAF6: TNF receptor associated factor 6.

Figure 4

Roles of m⁶A in cellular oxidative stress. All cells produce stress granules (SGs) under stress conditions. SGs mainly comprise mRNA and RBP, which can adjust mRNA translation and degradation. SGs are enriched with m⁶A mRNAs, and YTHDF1 plays a key role in SG formation and mRNA recruitment to SGs. In hippocampal neurons, Fto overexpression promotes an inward Ca²⁺ current (shown with gray arrow), causing mitochondrial damage and oxidative stress. Mettl3 KO also leads to oxidative stress and activates the caspase pathway. The activation of this pathway causes apoptosis, affecting the nervous system and memory. Created using Microsoft PowerPoint 2019. Red plus sign (+): positive effect or promoted. FTO: Fat mass and obesity-associated; KO: knockout protein; METTL3: methyltransferase like-3; RBP: RNA binding; SGs; stress granules; YTHDF1: YT521-B homology domain-containing family protein 1.

Figure 5

Roles of m⁶A in NSCs at different stages. In aNSCs, Fto knockout has different effects at different stages, manifesting poor differentiation in the short term and neurogenesis inhibition in the long term. Ythdf2 knockout results in a similar presentation, manifesting low NSC activity during the early developmental stage after birth and promoting differentiation during the embryonic stage and poor differentiation in induced pluripotent stem cells. Created using Microsoft PowerPoint 2019. Red plus sign (+): Positive effect or promoted; red minus sign (–): negative effect or inhibited; gray arrow: gene knockout in cell. aNSCs: Adult neural stem cells; NSCs: neural stem cells; YTHDF2: YT521-B homology domain-containing family protein 2.

Figure 6

Roles of m⁶A in memory. METTL3 participates in m⁶A formation. m⁶A promotes mRNA expression, leading more ARC/cFOS or IEG expression, which have positive effects on memory consolidation. YTHDF1 binding to m⁶A on mRNA promotes the translation of protein involved in memory formation and synaptic plasticity, enhancing learning and memory. Created using Microsoft PowerPoint 2019. Red plus sign (+): Positive effect or promoted. ARC: Activity-regulated cytoskeleton-associated protein; IEG: immediate early gene; METTL3: Methyltransferase like-3; YTHDF1: YT521-B homology domain-containing family protein 1.