m6A Methyltransferase METTL3 Reduces Hippocampal Neuron Apoptosis in a Mouse Model of Autism Through the MALAT1/SFRP2/Wnt/β-catenin Axis

Abstract

Objective Hippocampal neuron apoptosis contributes to autism, while METTL3 has been documented to possess great potentials in neuron apoptosis. Our study probed into the role of METTL3 in neuron apoptosis in autism and to determine the underlying mechanism.Methods Bioinformatics analysis was used to analyze expressed genes in autism samples. Institute of Cancer Research mice were treated with valproic acid to develop autism models. The function of METTL3 in autism-like symptoms in mice was analyzed with behavioral tests and histological examination of their hippocampal tissues. Primary mouse hippocampal neurons were extracted for in vitro studies. Downstream factors of METTL3 were explored and validated.Results METTL3, MALAT1, and Wnt/β-catenin signaling were downregulated, while SFRP2 was upregulated in the hippocampal tissues of a mouse model of autism. METTL3 stabilized MALAT1 expression by promoting m6A modification of MALAT1. MALAT1 promoted SFRP2 methylation and led to reduced SFRP2 expression by recruiting DNMT1, DNMT3A, and DNMT3B to the promoter region of SFRP2. Furthermore, SFRP2 facilitated activation of the Wnt/β-catenin signaling. By this mechanism, METTL3 suppressed autism-like symptoms and hippocampal neuron apoptosis.Conclusion This research suggests that METTL3 can reduce autism-like symptoms and hippocampal neuron apoptosis by regulating the MALAT1/SFRP2/Wnt/β-catenin axis.

METTL3 inhibits BMSC apoptosis and facilitates osteonecrosis repair via an m6A-IGF2BP2-dependent mechanism

“…Chen et al demonstrated that METTL3 could inhibit neuronal apoptosis by inhibiting the NFκB signaling pathway [ 37 ]. Ming et al demonstrated that METTL3 could alleviate hippocampal neuronal apoptosis by activating the Wnt signaling pathway [ 38 ]. However, whether METTL3 can reduce apoptosis of BMSCs by regulating some signaling pathways besides m6A modification remains to be further studied.…”

The Regulatory Network of METTL3 in the Nervous System: Diagnostic Biomarkers and Therapeutic Targets

“…Autism spectrum disorder (ASD) is one of the most common neurodevelopmental disorders, and hippocampal neuron apoptosis is greatly associated with the occurrence of ASD [ 38 ]. Ming et al reported that METTL3 was significantly downregulated in the hippocampal tissue of a mouse model of ASD, which facilitated the m6A modification of MALAT1 and subsequent stabilization of MALAT1 expression [ 39 ]. Next, MALAT1 decreased the expression of SFRP2 by recruiting DNMT1, DNMT3A, and DNMT3B to the SFRP promoter region, and SFRP2 finally promoted the activation of Wnt/β-catenin signaling.…”

“…Next, MALAT1 decreased the expression of SFRP2 by recruiting DNMT1, DNMT3A, and DNMT3B to the SFRP promoter region, and SFRP2 finally promoted the activation of Wnt/β-catenin signaling. Mechanically, downregulation of METTL3 triggered hippocampal neuron apoptosis by regulating the MALAT1/SFRP2/Wnt/β-catenin axis to trigger ASD occurrence and development [ 39 ] ( Figure 2 ).…”

LncRNAs and CircRNAs as Strategies against Pathological Conditions Caused by a Hypoxic/Anoxic State

“…However, it has recently gained interest in neurological research due to its involvement in nuclear organization and the regulation of apoptosis. MALAT1 is linked to neurological disorders such as Alzheimer's [102], Parkinson's [103], and autism [104]. Studies have also associated MALAT1 with hypoxic/anoxic conditions; it increases under H/I conditions, as observed in OGD models, and acts as a sponge for several miRNAs, including miR-429, miR-200c-3p, and miR-126.…”