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. 2021 May 19;9:656849. doi: 10.3389/fcell.2021.656849

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.