Alternative Splicing
alternative splicing
Dr Nikolas Nikolaou
Regulation of pre-mRNA splicing plays a significant role in neurons by diversifying the proteome and modulating gene expression during development and in response to physiological cues. Although most pre-mRNA processing reactions are thought to occur in the nucleus, numerous RNA splicing regulators are also found in neurites, however, very little is known about their extra-nuclear functions. We have recently shown that the non-nuclear pool of a major spliceosome component (SNRNP70) modulates the production of alternative spliced mRNA isoforms essential for motor connectivity and protects transcripts from degradation. This project aims to investigate the extra-nuclear activities of SNRNP70 in the context of neuronal connectivity in zebrafish. The ease of genetic manipulations together with the translucency and small size of their offspring allows us to monitor neural cell behaviour and function and observe changes in neuronal connectivity. We will use a range of genetic tools, including transgenic over-expression of cytoplasmic SNRNP70 and nuclear-only SNRNP70 zebrafish knock-in lines to establish developmental functions attributed to the cytoplasmic pool of SNRNP70. The results from this project will contribute to our understanding of how local RNA metabolism in axons contributes to the normal development of neural connections in the brain.
NF1 exon 51 alternative splicing: functional implications in Central Nervous System (CNS) Cells
Alternative Splicing and Isoforms: role in brain function and pathology
Targeting alternative splicing of SYNGAP1 using antisense oligonucleotides
Epigenetic regulation of alternative splicing in the context of cocaine reward
Neuronal alternative splicing is a key gene regulatory mechanism in the brain. However, the spliceosome machinery is insufficient to fully specify splicing complexity. In considering the role of the epigenome in activity-dependent alternative splicing, we and others find the histone modification H3K36me3 to be a putative splicing regulator. In this study, we found that mouse cocaine self-administration caused widespread differential alternative splicing, concomitant with the enrichment of H3K36me3 at differentially spliced junctions. Importantly, only targeted epigenetic editing can distinguish between a direct role of H3K36me3 in splicing and an indirect role via regulation of splice factor expression elsewhere on the genome. We targeted Srsf11, which was both alternatively spliced and H3K36me3 enriched in the brain following cocaine self-administration. Epigenetic editing of H3K36me3 at Srsf11 was sufficient to drive its alternative splicing and enhanced cocaine self-administration, establishing the direct causal relevance of H3K36me3 to alternative splicing of Srsf11 and to reward behavior.
Alternative splicing of Cav2.1 EF-hand contributes to the tightness of calcium influx-neurotransmitter release coupling at mouse cerebellar synapses
FENS Forum 2024
Extending MALAT1 activity to the modulation of LSD1 alternative splicing: A novel cell-autonomous mechanism devoted to neuronal homeostasis
FENS Forum 2024