MicroRNAs of the RPE are essential for RPE differentiation and photoreceptor maturation (mRNA)

Dysfunction of the retinal pigmented epithelium (RPE) results in degeneration of photoreceptors and vision loss and is correlated with common blinding disorders in humans. Although many protein-coding genes are known to be expressed in RPEs and important for their development and maintenance, virtually nothing is known about the in vivo roles of non-protein coding transcripts in RPEs. The expression patterns of microRNAs (miRNAs) have been analyzed in a variety of ocular tissues, and few were implicated to play role in RPE based on studies in cell lines. Herein, through RPE specific conditional mutagenesis of Dicer1 or DGCR8, the importance of miRNA for RPE differentiation was uncovered. Interestingly, miRNAs were found to be dispensable for maintaining the RPE fate and survival, and yet they are essential for acquisition of important RPE properties such as the expression of genes involved in the visual cycle pathway, pigmentation and cell adhesion. Importantly miRNAs of the RPE were found to be required for maturation of the adjacent photoreceptors, specifically for the morphogenesis of the outer segments. The profiles of miRNA and mRNA altered in the Dicer1 deficient RPE point to a key role of miR-204 in regulation of RPE differentiation program in vivo and uncovers the importance of additional novel RPE miRNAs. The study exposes the combined regulatory activity of miRNAs of the RPE, which is required for RPE differentiation and for the development of the adjacent neuroretina. Effect of Dicer 1 deficiency on RPE miRNA and mRNA.视网膜色素上皮（retinal pigmented epithelium, RPE）功能异常会导致光感受器变性与视力丧失，并与人类常见的致盲性眼病相关。尽管已知诸多编码蛋白的基因在RPE中表达且对其发育与维持至关重要，但目前学界对非编码转录本在RPE中的体内功能几乎一无所知。已有研究对多种眼组织中的微小RNA（microRNAs, miRNAs）表达模式进行了分析，但基于细胞系的研究极少提示miRNAs在RPE中发挥生理功能。本研究通过针对RPE的Dicer1或DGCR8特异性条件诱变实验，揭示了miRNAs对RPE分化的关键作用。有趣的是，miRNAs并非维持RPE细胞命运与存活所必需，但却是RPE获得核心特性的必备条件——这些特性包括视觉循环通路相关基因的表达、色素沉着以及细胞黏附。尤为重要的是，RPE来源的miRNAs对邻近光感受器的成熟不可或缺，尤其对外节的形态发生具有决定性作用。Dicer1缺陷型RPE中发生显著改变的miRNA与mRNA表达谱，提示miR-204在体内调控RPE分化程序中扮演核心角色，同时也揭示了其他新型RPE相关miRNAs的重要性。本研究阐明了RPE来源miRNAs的协同调控功能，该功能既是RPE分化的必要条件，也是邻近神经视网膜发育的关键支撑。Dicer1缺陷对RPE中miRNA与mRNA的影响