Mettl3-Mediated m6A Modification is Essential for Visual Function and Retinal Photoreceptor Survival

Area of Science:

• Epigenetics
• Molecular Biology
• Neuroscience

Background:

• N6-methyladenosine (m6A) is a prevalent mRNA modification regulating gene expression.
• METTL3 is the key enzyme in m6A methylation and essential for retinal development.
• The specific role of METTL3 in mature photoreceptor cells is not well understood.

Purpose of the Study:

• To investigate the in vivo function of METTL3 in mature photoreceptor cells.
• To determine the impact of Mettl3 deletion on retinal structure and function.

Main Methods:

• Conditional knockout of Mettl3 in rod and cone photoreceptor cells.
• Assessment of retinal structure, visual function, and gene/protein expression.
• Multi-omics analyses to identify Mettl3 target genes.

Main Results:

• Mettl3 deletion in rod cells caused progressive retinal degeneration, shortened outer segments, and reduced disk membrane proteins.
• Mettl3 deficiency in cone cells led to gradual cone opsin degeneration.
• Knockout decreased METTL14 expression and global m6A levels, downregulating 10 key target genes and causing photoreceptor death.

Conclusions:

• METTL3 plays a critical role in maintaining the function of retinal photoreceptor cells.
• m6A modification regulated by METTL3 is essential for photoreceptor survival and function.
• This study elucidates the mechanisms of m6A modification in photoreceptors.