Thursday, May 2, 2024
5/2/2024
Project Summary Regulation of RNA metabolism is emerging as a major regulatory hub for gene expression control in tissues like the brain and the muscle, which don't undergo cell division. Therefore, it is not surprising that there is a strong link between perturbation of RNA metabolism and a number of muscular and neurodegenerative diseases including myotonic dystrophy (MD) and amyotrophic lateral dystrophy (ALS). For example, MD- 1 is provoked by expansions of CTG repeats, which result in the sequestration of the splicing factor MBNL1 encoded by the gene muscleblind-1. MBNL1 and another member of the MBL family (MBNL2) have important and overlapping functions in RNA processing and transport, in particular in muscle and neurons. Circular RNAs (circRNAs) are a highly abundant, not well-characterized type of non-coding RNA. These RNAs are generated by circularization of specific exons, and their functionality is still controversial. Recent work from my laboratory has demonstrated that circRNA production competes with pre-mRNA splicing, suggesting that circRNAS are general cis regulators of gene expression. We found by study of MBL, the Drosophila homolog of MBNL1, that this protein regulates the production of a subset of circRNAs, including one generated from its own locus (circMbl). Strikingly, we noticed that the same exon of MBNL1 generates circRNAs in humans and that circMbl production in mammals can also be induced by MBL. Additional unpublished work from my lab demonstrates that a subset of circRNAs is translated. One of these translated circRNAs is circMbl. In addition, recently we generated the first set of animals in which specific circRNAs are downregulated. Many circRNA knockdown strains display strong developmental and physiological phenotypes, demonstrating for the first time functionality of circRNA molecules in vivo. circMbl knockdown leads to male embryonic lethality, defects in wing posture, and deficits in synaptic vesicular function. Here we aim to unravel the molecular and physiological implications of circMbl production and function. This work will result in pioneer functional characterization of circRNAs in vivo and will be key for understanding how MBL production and function is regulated in vivo. For doing so we will: Characterize the functional relationship between MBL and circMbl; determine spatial, temporal, and functional requirements of circMbl expression and determine molecular mechanism of action of circMbl during development and in adults. This project will illuminate essential regulatory mechanisms of mbl expression and function, processes intimately related to MD pathogenesis. In addition, this project is both technically and intellectually innovative in its analysis of the roles of circRNAs in central aspects of physiology, and behavior. Our project builds on strong preliminary results and the unique and constantly evolving expertise of our group.
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