Related Experiment Video
Updated: May 8, 2025
Immunohistochemical Detection of 5-Methylcytosine and 5-Hydroxymethylcytosine in Developing and Postmitotic Mouse Retina
Published on: August 29, 2018
Mettl3-Mediated m6A Modification is Essential for Visual Function and Retinal Photoreceptor Survival
Xiaoyan Jiang1, Kuanxiang Sun1, Yudi Fan1
1The Sichuan Provincial Key Laboratory for Human Disease Gene Study and Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
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.
Insights
METTL3 is crucial for maintaining retinal photoreceptor function. Its absence causes progressive degeneration in rod and cone cells, impacting vision and leading to cell death.
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.
Related Concept Videos
01:22Photoreceptors and Visual Pathways
02:04Covalently Linked Protein Regulators
These groups modify specific amino acids in a protein....