FIGURE 1.

Biogenesis and (putative) functions of Circular RNAs (circRNAs) in neurons. Schematic representation of a neuron, indicating established (turquoise) and putative (purple) general and neuron-specific functions of circular RNAs (circRNAs): (1) circRNAs such as CDR1as (Cerebellar degeneration-related protein 1 antisense) and SRY (Sex determining region Y) have binding sites for specific miRNAs, e.g., miR-7. By binding these miRNAs they act as ‘miRNA sponges’ and inhibit miRNA function. (2) circRNAs may affect neurite outgrowth and neuronal migration. For example, ectopic CDR1as expression causes migration defects in vitro. (3) miR-671 can bind CDR1as to induce AGO-mediated cleavage of this circRNA. This may result in the local release of other miRNAs bound by CDR1as. (4) Various RNA-binding proteins (RBPs) bind circRNAs. For example, MBL (muscleblind) can bind to its own circRNA. QKI (Quaking) and ADAR1 (Adenosine deaminase acting on RNA 1) bind circRNAs to regulate circRNA biogenesis (see box titled circRNA biogenesis). circRNAs may ‘sponge’ RBPs (such as TDP-43) in the nucleus to regulate gene expression. (5) Binding of RBPs by circRNAs may facilitate RBP transport to distal compartments in neurons, e.g., synapses. (6) circRNAs have been proposed to act as scaffolds for protein complex assembly. By binding multiple RBPs, circRNAs might facilitate stable interactions between proteins. (7) Exon-intron circRNAs (EIciRNAs) are associated with RNA polymerase II (Pol II) in the nucleus. EIciRNAs recruit Pol II to regulate host gene transcription via U1 snRNA. (8) It has been proposed that small peptides and/or proteins may be generated from circRNAs in the cytoplasm. (9) The expression of certain circRNAs is affected by neuronal activity. (10) circRNAs are present in synaptic vesicles. (11) circRNAs are present in extracellular vesicles and could act as long range signaling molecules. RCM, reverse complementary matches; Pol II, RNA polymerase II; AGO, Argonaute.