NeuroASPECT · Neuronal Alternative Splicing and RNA-Editing Crosstalk

Neuronal Alternative Splicing and RNA-Editing Crosstalk

One of the most intriguing questions in biology is to understand how in multicellular organisms the same genomic information can give rise to different cell types and tissues with distinct properties and functions. In particular, the mammalian central nervous system is a complex network of cells that relies on a tight regulation of gene expression that involves the coordination of post-transcriptional RNA mechanisms, such as alternative splicing (AS) and RNA-editing to boost genomic information and increase the repertoire of transcripts. Despite that RNA processing pathways present their highest prevalence in brain an integral view of the extent, evolutionary conservation and functional impact of neural regulated events is still missing. Our project can be divided in three main parts, each of those targeting three objectives. Generation of an extensive catalogue of tissue-specific alternative splicing events and RNA-editing sites, with special emphasis of those derived from neural tissues, of fifteen bilaterian species spanning more than 500 million years of evolution. Assess the evolutionary conservation of neural regulated events across all the species, highlighting those that are conserved between mammals and other species and therefore suggesting a functional role for these events in the physiology of the mammalian nervous system. Test the biological impact of highly conserved neural regulated events in the development and/or physiology of the nervous system. Overall, our work resulted in valuable conclusions. First, by making use of our extensive catalogue of tissue-specific AS events of fifteen species, we have found that AS is a prevalent molecular tool used by the nervous system of bilateria, suggesting an ancestral role of this post-transcriptional mechanism to increase transcript diversity in neurons. Moreover, we found that the AS events from neural samples present higher evolutionary conservation than other tissues tested, with some of them even preceding the chordate ancestor and implying a functional and ancestral role of these AS events in neurons development and function. Finally, by testing some of these neural conserved AS events in the model system Drosophila melanogaster, we determined that defects in the inclusion of these events in the nervous system of the fly can result in severe neurological defects. Therefore, we expect that our comprehensive catalogue of tissue specific AS events in conjunction with their evolutionary conservation provide a robust source for the scientific community to study the role of tissue regulated AS in normal conditions and disease in the nearby future.

Data: CORDIS, © European Union