TABLE 1.
m6A mRNA methylation factors and their role in brain development and function.
Effector | Experimental manipulation | Phenotype | Mechanisms | References |
Neurogenesis | ||||
METTL3 | Mettl3fl/fl; Nestin-Cre | Prolongation of the cell cycle of RGCs and protraction of embryonic cortical neurogenesis | m6A depletion caused increased stability of NSC transcripts | Yoon et al. (2017) |
METTL14 | Mettl14fl/fl; Nestin-Cre | Reduced NSC proliferation and precocious NSC differentiation; loss of late-born neurons during cortical neurogenesis | Stabilization of CBP and p300 transcripts; H3K27me3-mediated transcription suppression of NSC proliferation genes; upregulation of H3K27ac in differentiation-related genes | Wang Y. et al. (2018) |
RBM15 | OE of RBM15 | NSC delamination | Suppression of BAF155-dependent gene expression | Xie et al. (2019) |
FTO | KO of FTO | Decrease in adult NSC proliferation and defective hippocampal neurogenesis | Impairment of BDNF and MAPK signaling | Li L. et al. (2017); Spychala and Ruther (2019) |
YTHDF2 | Ythdf2 fl/fl; Cre (ubiquitously) | Decreased proliferation and differentiation capabilities of NSCs; less Tbr2+ bIPs; Reduced CP thickness | Promotion of m6A-dependent degradation of neurodevelopment-related transcripts | Li M. et al. (2018) |
FMRP | KO of Fmr1 | Nuclear retention of neurogenic mRNAs; prolonged cell cycle progression in the postnatal mouse brain | Unknown | Edens et al. (2019) |
Exosc10 | Exosc10fl/fl; Foxg1-Cre; Emx1-Cre | Apoptosis-mediated cortical agenesis | Mediates degradation of Bbc3 and Aen mRNAs, which are effectors of apoptosis | Ulmke et al. (2021) |
Gliogenesis | ||||
METTL14 | Mettl14fl/fl; Olig2-Cre | Decrease in oligodendrocytes maturation; cortical hypomyelination | Alters alternative splicing and expression of Nfasc155 | Xu et al. (2020) |
METTL14 | Mettl14; Nestin-Cre | Reduced number of s100β+ astrocytes | Unknown | Yoon et al. (2017) |
FTO | FTOfl/fl; Olig2-Cre; Nestin-Cre | Loss of OPCs and Sox10+ cells; cortical hypomyelination | Promotes Olig2 mRNA degradation | Wu et al. (2019) |
PRRC2A | Prrc2a; Nestin-Cre; Olig2-Cre | Loss of OPCs and mature oligodendrocytes; cortical hypomyelination | Gene targeting of Prrc2a by olig2 mRNA | Wu et al. (2019) |
PRRC2A | Prrc2a; Nestin-Cre; | Reduced proliferation capacity and number of astrocytes | Competitive expression with YTHDF2 | Wu et al. (2019) |
Axonogenesis, dendritogenesis, synaptic plasticity | ||||
YTHDF1 YTHDF3 | KD of Ythdf1 and Ythdf3 | Abnormal dendritic spine morphology | Inhibition of Apc mRNA translation | Merkurjev et al. (2018) |
METTL14 | Mettl14fl/fl; D1R-Cre | Abnormal excitability of striatal neurons | Unknown | Koranda et al. (2018) |
FTO | KO of FTO | Defective synaptic plasticity | Unknown | Hess et al. (2013) |
YTHDF1 YTHDF3 | KD of Ythdf1 and Ythdf3; CRISPR/Cas9-based KO of Ythdf1 | Suppression of neuronal excitability | Not clear | Merkurjev et al. (2018); Shi et al. (2018) |
Learning and behavior | ||||
METTL3 | OE of METTL3 | Improved long-term memory consolidation | Unknown | Zhang Z. Y. et al. (2018) |
METTL14 | Mettl14fl/fl; D1R-Cre | Impaired striatum-mediated behavior patterns | Unknown | Koranda et al. (2018) |
FTO | CRISPR/Cas9 or shRNA-mediated KD of FTO | Learning disabilities; defective memory processing and verbal fluency | Not clear | Ho et al. (2010); Benedict et al. (2011); Widagdo et al. (2016); Li L. et al. (2017); Walters et al. (2017); Sun et al. (2019) |
PRRC2A | Prrc2a; Nestin-Cre; Olig2-Cre | Cognitive defects due to cortical hypomyelination | Unknown | Wu et al. (2019) |
YTHDF1 | CRISPR/Cas9-based KO of Ythdf1; KD of Ythdf1 | Defective long-term potentiation and synaptic transmission in hippocampus; behavioral defects | Unknown | Shi et al. (2018) |
Circadian clock | ||||
METTL3 | KD of Mettl3 | Elongation of circadian period | Defective processing of Per2 and Arntl (clock genes) mRNAs | Fustin et al. (2013) |
Stress response | ||||
FTO | FTOfl/fl; Camk2a-Cre; Nex-CreERT2 | Reduced ability to cope with stress | Unknown | Engel et al. (2018) |
METTL3 | Mettl14fl/fl; Camk2a-Cre; Nex-CreERT2 | Reduced ability to cope with stress | Unknown | Engel et al. (2018) |
KO, knockout; KD, knockdown; OE, overexpression; fl/fl, double floxed; RGCs, radial glial cells; OPCs, oligodendrocyte precursor cells; NSCs, neural stem cells; CRISPR, clustered regularly interspaced short palindromic repeats; m6A, N6-methyladenosine.