PUBLICATION

METTL3-dependent m6A modification of PSEN1 mRNA regulates craniofacial development through the Wnt/β-catenin signaling pathway

Authors
Ma, L., Zhou, X., Yao, S., Zhang, X., Mao, J., Vona, B., Fan, L., Lou, S., Li, D., Wang, L., Pan, Y.
ID
ZDB-PUB-240321-10
Date
2024
Source
Cell Death & Disease   15: 229229 (Journal)
Registered Authors
Keywords
none
MeSH Terms
  • Methyltransferases/genetics
  • Methyltransferases/metabolism
  • Animals
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • Methylation
  • RNA, Messenger/genetics
  • RNA, Messenger/metabolism
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
  • beta Catenin*/genetics
  • beta Catenin*/metabolism
  • Wnt Signaling Pathway*/genetics
  • Presenilin-1/genetics
  • Presenilin-1/metabolism
(all 15)
PubMed
38509077 Full text @ Cell Death Dis.
Abstract
Craniofacial malformations, often associated with syndromes, are prevalent birth defects. Emerging evidence underscores the importance of m6A 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 m6A 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 m6A-modified PSEN1, while decreased METTL3-mediated m6A 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.
Genes / Markers
Figures
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Expression
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Phenotype
No data available
Mutations / Transgenics
No data available
Human Disease / Model
No data available
Sequence Targeting Reagents
No data available
Fish
No data available
Antibodies
Name Type Antigen Genes Isotypes Host Organism
Ab1-gsk3monoclonal
    		Rabbit
    Ab1-ythdf1polyclonal
      		IgGRabbit
      Ab3-mettl3monoclonal
        		IgGRabbit
        Ab3-sox3polyclonalIgGRabbit
        Ab3-sox10polyclonalIgGRabbit
        Ab4-psen1monoclonal
          		IgGRabbit
          Ab10-ctnnbpolyclonal
            		Rabbit
            Ab13-sox2monoclonalIgG1Mouse
            1 - 8 of 8
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            Orthology
            No data available
            Engineered Foreign Genes
            No data available
            Mapping
            No data available
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            Citation
            Ma, L., Zhou, X., Yao, S., Zhang, X., Mao, J., Vona, B., Fan, L., Lou, S., Li, D., Wang, L., Pan, Y. (2024) METTL3-dependent m6A modification of PSEN1 mRNA regulates craniofacial development through the Wnt/β-catenin signaling pathway. Cell Death & Disease. 15:229229.