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Final Report Summary - NEUROCRYSP (Regulation of cryptic splice sites in neuronal differentiation and disease)

NeuroCRYSP research project has studied splicing, in particular a complex splicing mechanism in vertebrates brain named Recursive Splicing. This mechanism allows splicing of long introns in the brain in a two-step model, as previously proposed for Drosophila. However, in vertebrates the process starts with the recognition of a cryptic RS-exon within the long intron. After splicing to its preceding intron, the RS-exon is skipped and both the upstream and downstream exons are joined together. The researcher in NeuroCRYSP project has contributed with many experimental approaches to understand recursive splicing mechanism in brain. These results were published in Nature journal in May 2015 and have greatly expanded knowledge about splicing mechanism in the scientific community. Moreover, in order to understand the function of recursive splicing further, the researcher has designed genome-editing experiments (experimental work performed by PhD rotation student Ms Andrea Elser) in order to disrupt recursive splice sites in induced pluripotent stem cells (iPSCs) and study their neuronal differentiation pattern.
Recursive splicing generally ends up with RS-exon skipped from mature RNA. However, in some situations, such as within non-canonical minor isoforms expressed from alternative promoters, RS-exons can become included in mature RNA. Based on this observation, a new hypothesis was generated about the role of recursive splicing mechanism in the regulation of canonical splicing. The researcher performed many experimental and bioinformatics approaches to conclude that recursive splicing can affect splicing of many canonical exons in the transcriptome, which contain a 5’ splice site motif at the start of the exon. Moreover, the researcher found that recursive splicing inhibition by Exon Junction Complex (EJC) explains why canonical RS-exons normally remain included in mRNAs. We plan to submit these results soon to Cell journal. Mutations in genes coding different EJC components have been associated with rare diseases and neurodevelopmental disorders. The discovery of the involvement of EJC in regulation of recursive splicing is essential for future studies that focus on the molecular mechanism of these disorders and will potentially help to design therapeutic approaches to treat these diseases.

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United Kingdom
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