Sponges and Predators in the Small RNA World

MicroRNAs (miRNAs) are 20- to-24-nucleotide (nt)-long RNAs that guide Argonaute proteins to silence mRNA expression in animal and plant cells ( 1 – 3 ). Similarly to bacterial trans-encoded small RNAs (sRNAs), miRNAs act by establishing imperfect base-pair interactions with seed sequences that can be as short as 6 to 8 nt. Seeking ways to selectively control miRNA activity in vivo, a decade ago Ebert and coworkers engineered transcripts containing multiple tandemly arranged target sites for one or more miRNAs and had these constructs expressed at high levels in transfected mammalian cells ( 4 ). They found the exogenous RNAs to have the ability to sequester (“soak up”) the miRNAs, relieving the regulation of their natural targets. The authors termed the artificial transcripts “microRNA sponges.” At about the same time, a study on the mechanism responsible for inhibiting the activity of a miRNA (miR399) in plant cells identified an endogenous noncoding RNA, named IPS1, that could base-pair with miR399 and compete for its binding to the primary target ( 5 ). This indicated that a natural RNA could have sponge-like activity and that target site amplification was not required for this effect. Following these initial findings, several examples of miRNA target mimicry have been described involving different types of coding and noncoding RNAs ( 6 , 7 ), including some of viral origin ( 8 , 9 ). Particularly noteworthy is the case of the circular antisense RNA named CDR1as, highly expressed in human and mouse brain, which harbors as many as 74 potential target sites for the miR-7 miRNA and thus closely fulfills the original definition of a sponge ( 10 ). Recent evidence showed CDR1as to be a highly efficient miR-7 sponge in vivo: in cells lacking CDR1as, deregulation of miR-7 networks leads to profound defects in brain development and function ( 11 ).