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Exploring the role of circular RNAs in neuronal function

Circular RNAs (circRNAs) have been recently shown to be a relatively abundant, developmentally regulated class of alternatively-spliced, covalent-closed-circle RNAs produced by the ‘back-splicing’ of adjacent exons from linear pre-messenger RNAs (pre-mRNAs). One of the most significant and exciting observations made by recent studies is that circRNAs were substantially enriched in neuronal human cell culture, and mice and drosophila brains relative to other cell types and tissues, and exhibited developmental- and activity-dependent regulation of expression levels. The exquisite amount of developmental- and activity- dependent regulation exhibited by these particular circRNAs strongly suggests the possibility of important roles in neuronal development, function and plasticity, however, to date these functions have not yet been revealed.

With this in mind, the O’Connell Lab aims to test the hypothesis that a number of unidentified cis- and trans- acting factors governing the biogenesis and the function of neuronal circRNAs exist, and collectively these are involved in the regulation of neuronal development and plasticity. This project will harness RNA-targeting CRISPR tools developed during my postdoctoral research (such as RCas9 and C2c2) to specifically manipulate a subset of circRNAs from a neuronal differentiation cell culture model. The specificity and versatility of these RNA-targeting CRISPR tools make them the useful for the study of circRNA function.

The results of this work will represent a major advance in the understanding of circRNA function in neurons and have the potential to yield novel RNA-targeted therapies for the treatment of neurological and neuromuscular diseases. One can imagine directly introducing particular circRNAs or circRNA-targeting molecules (e.g. RNAi or RCas9) into neurons to modulate neuronal function.