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Immunohistochemical Detection of 5-Methylcytosine and 5-Hydroxymethylcytosine in Developing and Postmitotic Mouse Retina
Published on: August 29, 2018
Mettl14-mediated m6A modification is essential for visual function and retinal photoreceptor survival
Yeming Yang1,2,3, Ping Shuai1,2, Xiao Li1,2
1Health Management Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 61007, Sichuan, China.
Background:
As the most abundant epigenetic modification of eukaryotic mRNA, N6-methyladenosine (m6A) modification has been shown to play a role in mammalian nervous system development and function by regulating mRNA synthesis and degeneration. However, the role of m6A modification in retinal photoreceptors remains unknown.
Results:
We generated the first retina-specific Mettl14-knockout mouse models using the Rho-Cre and HRGP-Cre lines and investigated the functions of Mettl14 in retinal rod and cone photoreceptors. Our data showed that loss of Mettl14 in rod cells causes a weakened scotopic photoresponse and rod degeneration. Further study revealed the ectopic accumulation of multiple outer segment (OS) proteins in the inner segment (IS). Deficiency of Mettl14 in cone cells led to the mislocalization of cone opsin proteins and the progressive death of cone cells. Moreover, Mettl14 depletion resulted in drastic decreases in METTL3/WTAP levels and reduced m6A methylation levels. Mechanistically, transcriptomic analyses in combination with MeRIP-seq illustrated that m6A depletion via inactivation of Mettl14 resulted in reduced expression levels of multiple phototransduction- and cilium-associated genes, which subsequently led to compromised ciliogenesis and impaired synthesis and transport of OS-residing proteins in rod cells.
Conclusions:
Our data demonstrate that Mettl14 plays an important role in regulating phototransduction and ciliogenesis events and is essential for photoreceptor function and survival, highlighting the importance of m6A modification in visual function.
Insights
N6-methyladenosine (m6A) modification, regulated by Mettl14, is crucial for retinal photoreceptor function. Loss of Mettl14 impairs phototransduction and ciliogenesis, leading to vision loss and photoreceptor degeneration.
Area of Science:
- Molecular Biology
- Epigenetics
- Neuroscience
Background:
- N6-methyladenosine (m6A) is the most abundant mRNA modification in eukaryotes.
- m6A regulates mRNA synthesis and degradation in the nervous system.
- The role of m6A in retinal photoreceptors is currently unknown.
Purpose of the Study:
- To investigate the function of Mettl14, an m6A writer, in retinal rod and cone photoreceptors.
- To elucidate the role of m6A modification in visual function.
Main Methods:
- Generated retina-specific Mettl14-knockout mouse models (Rho-Cre and HRGP-Cre).
- Analyzed photoreceptor function using electroretinography.
- Investigated protein localization and gene expression via transcriptomics and MeRIP-seq.
Main Results:
- Mettl14 deficiency in rods caused weakened scotopic photoresponse and degeneration, with protein mislocalization.
- Mettl14 deficiency in cones led to opsin mislocalization and cell death.
- Mettl14 depletion reduced m6A levels and expression of phototransduction and ciliogenesis genes, impairing protein transport.
Conclusions:
- Mettl14 is essential for photoreceptor function and survival by regulating phototransduction and ciliogenesis.
- m6A modification plays a critical role in maintaining visual function.
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