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.