| Description: |
Extracellular vesicles are known to play vital roles in intercellular communication across biological processes, including neuronal development. Our lab has recently identified the ability for the immediate early gene, Drosophila Arc1 (dArc1), to bind and encapsulate its own transcript via its viral-like Gag domain to initiate its transfer across the neuromuscular junction (NMJ) via EVs in a phenomenon described as the Viral-Like Synaptic Transfer of RNA (ViSyToR) pathway. Remarkably, this capsid formation and transfer is further conserved to the dArc1 mammalian ortholog, Arc. dArc1 was recently observed to interact with transcripts other than its own, including the transcript for the RNA splicing factor muscleblind (Mbl). Here, we demonstrate that this interaction is further conserved to Arc and the mammalian Mbl ortholog, mbnl1. Interestingly, this interaction is enhanced by neuronal stimulation both in mammalian neuronal cell culture and in the mouse hippocampus. Furthermore, we observe that mbnl1 is present within mammalian EVs but not within the Arc capsid and that ratios of EV-derived mbnl1 are altered by neuronal stimulation. At the Drosophila NMJ, we observe that MblA, a Mbl isoform, transfers across the synapse in EVs and this transfer is dependent on the presence of presynaptic dArc1. Finally, in a Drosophila model of myotonic dystrophy, we observe increased dArc1 accumulation at the NMJ while Mbl was reduced. Taken together, our results demonstrate the conservation of an activity dependent interaction between dArc1 and mbl that mediates postsynaptic accumulation of MblA, likely through EVs, and is disrupted by toxic RNA repeats. In conclusion, this dissertation provides insight into the EV mediated viral-like intercellular communication in the central nervous system. ; Neuroscience ; 2 years ; 2027-09-04 |