Purpose: N6-methyladenosine (m6A) modification, one of the most common epigenetic modifications in eukaryotic mRNA, has been shown to play a role in the development and function of the mammalian nervous system by regulating the biological fate of mRNA. METTL3, the catalytically active component of the m6A methyltransferase complex, has been shown to be essential in development of in the retina. However, its role in the mature retina remains elusive. In this study we aim to investigate the in vivo function of Mettl3 in the photoreceptor cells using a conditional knockout allele of Mettl3.
Methods: Deletion of Mettl3 in rod cells led to progressive retinal degeneration, including progressive retinal thinning, impaired visual function, shortened photoreceptor outer segments (OS), and reduced expression of disk membrane proteins. Similarly, Mettl3 deficiency in cone cells led to the gradual degeneration of cone opsins. Additionally, Mettl3 knockout significantly decreased the expression of the METTL14 subunit and overall m6A methylation levels in the retina.
Results: Multi-omics analyses revealed that Mettl3 deletion led to the downregulation of mRNA and protein levels of 10 key target genes in rod cells, ultimately resulting in the progressive death of photoreceptors. Mettl3 controls expression of its target genes by regulating their m6A modification, ultimately leading to rod cell death.
Conclusions: These findings highlight critical roles of METTL3 in maintaining retinal photoreceptor function and further elucidate the mechanisms of m6A modification in photoreceptors.