Mettl14-mediated m6A modification is essential for visual function and retinal photoreceptor survival

Abstract

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.

Mettl14-mediated m6A modification enhances the function of Foxp3+ regulatory T cells and promotes allograft acceptance

“…In this animal model, the Mettl14 allele is selectively depleted or reduced in Treg cells, and the western blot analysis showed the protein level of METTL14 was significantly abrogated in Treg cells isolated from either heterozygotes or homozygotes. Meanwhile, the expression of METTL3, the core component of the RNA methyltransferase complex, was also reduced to some extent, similar to a previous report ( 28 ). Moreover, compared to the littermate controls, a 60% to 90% decrease in FOXP3 expression was observed in Treg cells from Foxp3-Mettl14 f/+ and Foxp3-Mettl14 f/f cKO mice ( Figures 2A, B ).…”

Promoting Axon Regeneration By Inhibiting RNA N6-methyladenosine Demethylase ALKBH5

“…In contrast to the observations in DRG neurons, ALKBH5 expression was unchanged in the RGC following ONC, which may partially contribute to the different regenerative abilities between neurons in the PNS and CNS. Previous studies have reported that the methyltransferase METTL14 is essential for retinal photoreceptor survival, while inhibition of m6A demethylases FTO supports the survival of dopamine neurons (Selberg et al, 2021; Yang et al, 2022), suggesting that m6A plays important roles in neuronal survival. Consistent with these results, we revealed that Alkbh5 knockdown promotes RGC survival.…”

Cephalopod Sex Determination and its Ancient Evolutionary Origin

“…bimaculoides and E. scolopes of 381 million years (14). It was thus imperative to examine whether the orthologous chromosome in E. scolopes was functioning as a Z chromosome in that lineage.…”

“…Our evidence, when taken together, demonstrates that the O. bimaculoides Z chromosome is a genomic outlier with clear homology at the gene level and with respect to repeat content to chr20 in O. sinensis and to chr43 in E. scolopes . While the divergence time between O. bimaculoides and O. sinensis is relatively modest at approximately 34 million years, divergence between squids and octopus is much older, with an approximate divergence time between O. bimaculoides and E. scolopes of 381 million years ( 14 ). It was thus imperative to examine whether the orthologous chromosome in E. scolopes was functioning as a Z chromosome in that lineage.…”