Friday, December 6, 2024
12/6/2024
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 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 studying 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). Work from the previous period demonstrated that circRNAs generated from the mbl locus regulate gene expression, physiology and behavior. We found that these circRNAs act in cis and are part of a self-regulatory loop that limits MBL expression. In addition, we found that circMbl has functions in trans as knockdown (KD) of circMbl provokes several developmental, physiological and behavioral phenotypes which are distinct but related to the ones observed upon MBL KD. Together, our data demonstrates that circMbl and MBL work in related pathways but have distinct functions. Here we aim to unravel the molecular and physiological implications of circMbl production and function. This work will result in pioneering functional characterization of circRNAs in vivo and will be key for understanding how MBL production and function are regulated in vivo. For doing so we will: identify MBL- dependent and MBL-independent mechanisms of action of circMbl. We will follow by determining the physiological and neural roles of mbl and circMbl isoforms. This project will illuminate essential regulatory mechanisms of mbl expression and function. As or more importantly, 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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