Then, lariats that escape from debranching can lead to the formation of ciRNAs ( Zhang et al., 2013 Eger et al., 2018). This excised lariat undergoes internal back-splicing. In canonical splicing, a lariat intron is generated after the splicing of the linear pre-mRNA and isolated from the ultimate mRNA product. A pre-mRNA can generate linear RNA, lariat introns, Y-structure introns from trans-splicing, and circular exons through exon skipping ( Suzuki et al., 2006).

(1) They can be generated from intronic lariat precursors that escape from the debranching step of canonical linear splicing ( Figure 1A Zhang et al., 2013). These circRNAs can be generated in different manners. Due to their different origins, they have different names, such as exonic circRNA (or ecircRNA), intronic circRNA (or ciRNA), and exon–intron circRNA (or ElciRNA) ( Figure 1 Zhang et al., 2013 Guo et al., 2014 Li et al., 2015). Biogenesis, Properties, and Functions of circRNAs BiogenesisĬircular RNAs can be generated from different gene loci, such as coding and non-coding exons, introns, both exons and introns, or antisense or intergenic sequences. It has been demonstrated that circRNAs are abundant in the retina and play a role in biogenesis and various biological functions ( Wang et al., 2018a Chen et al., 2020c). As an extension of the brain and a part of the central nervous system (CNS), the retina is another option for investigators to study enigmas of circRNAs. For instance, circ-TTBK2 and circPCMTD1 act as sponges of miR-224-5p to promote glioma progression ( Zheng et al., 2017, 2019). In addition, circRNAs participate in many processes of neurological diseases. Furthermore, their expression is dramatically increased in the brain during the aging of multiple organisms ( Knupp and Miura, 2018). Recent genome-wide profiling of circRNAs has shown that numerous circRNAs are widely and dynamically expressed in the nervous system. CircRNAs exert their action mainly by acting as a miRNA sponge and functioning through a competing endogenous RNA (ceRNA) mechanism ( Hansen et al., 2013 Memczak et al., 2013), as well as acting as protein sponges or translating proteins ( Legnini et al., 2017). Due to the lack of 5′–3′ polarity and a polyadenylated tail, circRNAs are much more insusceptible than linear RNAs to degradation by exonuclease RNase R. Unlike messenger RNAs (mRNAs), circRNAs are mostly derived from different regions of gene loci in eukaryotes through a non-canonical splicing process called “back-splicing.” During back-splicing, the downstream 5′ splice site is covalently bonded to an upstream 3′ splice site in a reversed orientation. However, major recent studies have discovered that circRNAs have essential functions and play a novel regulatory role, especially in the nervous system ( Memczak et al., 2013), prompting interest from an increasing number of investigators from various fields. In this review, we highlight the current state of circRNA biogenesis, properties, function and the crucial roles they play in the CNS.įor many years, although proven to be present, circular RNAs (circRNAs) were overlooked as byproducts of splicing errors ( Sanger et al., 1976 Barrett and Salzman, 2016). Correspondingly, they also play an important role in the occurrence and progression of CNS diseases. Numerous studies have shown that circRNAs are enriched in the central nervous system (CNS) and play an important role in the development and maintenance of homeostasis. CircRNAs have a tissue-specific distribution and are evolutionarily conserved, and many circRNAs play important biological functions by combining with microRNAs and proteins to regulate protein functions and their own translation. They are generated most commonly from back-splicing of protein-coding exons. Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing, ChinaĬircular RNAs (circRNAs) are endogenous single-stranded RNAs characterized by covalently closed loop structures with neither 5′ to 3′ polarity nor poly(A) tails.

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