METTL3-dependent MA Modification of PSEN1 MRNA Regulates Craniofacial Development Through the Wnt/β-catenin Signaling Pathway

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2024 Mar 21

PMID 38509077

Authors

Lan Ma

Xi Zhou

Siyue Yao

Xinyu Zhang

Ji Mao

Barbara Vona

Liwen Fan

Shu Lou

Dandan Li

Lin Wang

Yongchu Pan

Affiliations

Soon will be listed here.

Abstract

Craniofacial malformations, often associated with syndromes, are prevalent birth defects. Emerging evidence underscores the importance of mA modifications in various bioprocesses such as stem cell differentiation, tissue development, and tumorigenesis. Here, in vivo, experiments with zebrafish models revealed that mettl3-knockdown embryos at 144 h postfertilization exhibited aberrant craniofacial features, including altered mouth opening, jaw dimensions, ethmoid plate, tooth formation and hypoactive behavior. Similarly, low METTL3 expression inhibited the proliferation and migration of BMSCs, HEPM cells, and DPSCs. Loss of METTL3 led to reduced mRNA mA methylation and PSEN1 expression, impacting craniofacial phenotypes. Co-injection of mettl3 or psen1 mRNA rescued the level of Sox10 fusion protein, promoted voluntary movement, and mitigated abnormal craniofacial phenotypes induced by mettl3 knockdown in zebrafish. Mechanistically, YTHDF1 enhanced the mRNA stability of mA-modified PSEN1, while decreased METTL3-mediated mA methylation hindered β-catenin binding to PSEN1, suppressing Wnt/β-catenin signaling. Pharmacological activation of the Wnt/β-catenin pathway partially alleviated the phenotypes of mettl3 morphant and reversed the decreases in cell proliferation and migration induced by METTL3 silencing. This study elucidates the pivotal role of METTL3 in craniofacial development via the METTL3/YTHDF1/PSEN1/β-catenin signaling axis.

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