N 6-methyladenosine (m6A) is the most prevalent mRNA internal modification and has been shown to regulate the development, physiology, and pathology of various tissues. However, the functions of the m6A epitranscriptome in the visual system remain unclear. In this study, using a retina-specific conditional knockout mouse model, we show that retinas deficient in Mettl3, the core component of the m6A methyltransferase complex, exhibit structural and functional abnormalities beginning at the end of retinogenesis. Immunohistological and single-cell RNA sequencing (scRNA-seq) analyses of retinogenesis processes reveal that retinal progenitor cells (RPCs) and Müller glial cells are the two cell types primarily affected by Mettl3 deficiency. Integrative analyses of scRNA-seq and MeRIP-seq data suggest that m6A fine-tunes the transcriptomic transition from RPCs to Müller cells by promoting the degradation of RPC transcripts, the disruption of which leads to abnormalities in late retinogenesis and likely compromises the glial functions of Müller cells. Overexpression of m6A-regulated RPC transcripts in late RPCs partially recapitulates the Mettl3-deficient retinal phenotype. Collectively, our study reveals an epitranscriptomic mechanism governing progenitor-to-glial cell transition during late retinogenesis, which is essential for the homeostasis of the mature retina. The mechanism revealed in this study might also apply to other nervous systems.
Keywords: developmental biology; glial cell; m6A; mouse; retinal development.
The retina is a layer in the eye that converts light into electrical signals, which allows us to see. It is a part of the central nervous system and is made of brain cells, such as neurons and supporting cells called glia. These supporting cells protect neurons, supply them with nutrients and maintain steady surrounding conditions. The retina shares many characteristics with other neural tissues, so it is useful for biologists to study these structures. One way for cells to control the activity of genes is by chemically modifying messenger RNA molecules. These alterations can affect various aspects of mRNA and the proteins that are ultimately produced. The most common mRNA modification, referred to as m6A, plays a key role in the development and healthy performance of various tissues. However, it is unclear whether m6A is involved in how glial cells in the retina develop. To address this question, Xin et al. studied the impact of blocking m6A in the retina of mice. These genetically modified mice displayed abnormalities as the retina developed. Analysis of the mRNA produced in single cells and the pattern of modifications revealed that m6A is involved in the development of glia. In particular, m6A helps to remove the mRNA associated with early-stage proto-glia, allowing the cells to mature and transition to their final form. The finding by Xin et al. that the m6A RNA modification is an essential part of retina development could help to understand eye diseases. In addition, this discovery may apply to other brain regions, and, in time, such work could lead to new treatments for neurodegenerative diseases.
© 2022, Xin et al.