m(6)A epitranscriptomic modification regulates neural progenitor-to-glial cell transition in the retina.
m(6)A epitranscriptomic modification regulates neural progenitor-to-glial cell transition in the retina.
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作者：
Xin Y;He Q;Liang H;Zhang K;Guo J;Zhong Q;Chen D;Li J;Liu Y;Chen S
N-6-甲基腺苷（m6 A）是最普遍的mRNA内部修饰，并已被证明可调节各种组织的发育、生理和病理。然而，m6 A表转录组在视觉系统中的功能仍不清楚。在这项研究中，使用视网膜特异性条件性基因敲除小鼠模型，我们表明，视网膜缺乏Mettl 3，m6 A甲基转移酶复合物的核心组成部分，表现出结构和功能异常开始在视网膜发生结束。视网膜发生过程的免疫组织学和单细胞RNA测序（scRNA-seq）分析显示，视网膜祖细胞（RPC）和Müller神经胶质细胞是主要受Mettl 3缺陷影响的两种细胞类型。scRNA-seq和MeRIP-seq数据的综合分析表明，m6 A通过促进RPC转录本的降解来微调从RPC到Müller细胞的转录组转变，RPC转录本的破坏导致晚期视网膜发生异常，并可能损害Müller细胞的神经胶质功能。晚期RPC中m6 A调节的RPC转录物的过表达部分地重现了Mettl 3缺陷型视网膜表型。总的来说，我们的研究揭示了一个epitranscriptomic机制，在视网膜发生后期，这是必不可少的成熟视网膜的稳态祖细胞到胶质细胞的过渡。这项研究揭示的机制也可能适用于其他神经系统。视网膜是眼睛中的一层，它将光转化为电信号，使我们能够看到。它是中枢神经系统的一部分，由脑细胞组成，如神经元和称为神经胶质的支持细胞。这些支持细胞保护神经元，为它们提供营养并维持稳定的环境条件。视网膜与其他神经组织有许多共同的特征，因此生物学家研究这些结构是有用的。细胞控制基因活性的一种方法是通过化学修饰信使RNA分子。这些改变可以影响mRNA和最终产生的蛋白质的各个方面。最常见的mRNA修饰，称为m6 A，在各种组织的发育和健康表现中起着关键作用。然而，目前还不清楚m6 A是否参与视网膜中神经胶质细胞的发育。为了解决这个问题，Xin等人研究了阻断m6 A对小鼠视网膜的影响。这些转基因小鼠在视网膜发育时表现出异常。对单细胞中产生的mRNA和修饰模式的分析表明，m6 A参与神经胶质的发育。特别是，m6 A有助于去除与早期原神经胶质细胞相关的mRNA，使细胞成熟并过渡到其最终形式。Xin等人发现m6 A RNA修饰是视网膜发育的重要组成部分，这可能有助于了解眼部疾病。此外，这一发现可能适用于其他大脑区域，而且，随着时间的推移，这些工作可能会导致神经退行性疾病的新疗法。
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. 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.