Abstract
Memory and learning involve activity-driven expression of proteins and cytoskeletal reorganization at new synapses, requiring posttranscriptional regulation of localized mRNA a long distance from corresponding nuclei. A key factor expressed early in synapse formation is Msp300/Nesprin-1, which organizes actin filaments around the new synapse. How Msp300 expression is regulated during synaptic plasticity is poorly understood. Here, we show that activity-dependent accumulation of Msp300 in the postsynaptic compartment of the Drosophila larval neuromuscular junction is regulated by the conserved RNA binding protein Syncrip/hnRNP Q. Syncrip (Syp) binds to msp300 transcripts and is essential for plasticity. Single-molecule imaging shows that msp300 is associated with Syp in vivo and forms ribosome-rich granules that contain the translation factor eIF4E. Elevated neural activity alters the dynamics of Syp and the number of msp300:Syp:eIF4E RNP granules at the synapse, suggesting that these particles facilitate translation. These results introduce Syp as an important early acting activity-dependent regulator of a plasticity gene that is strongly associated with human ataxias.
Highlights
Activity-dependent neuronal plasticity is the cellular basis of memory and learning, involving the formation of new synapses and cytoskeletal remodeling in response to neuronal activity (West and Greenberg, 2011)
Baseline and activity-dependent expression of Msp300 are posttranscriptionally regulated by Syp In response to elevated neuronal activity, Msp300 is rapidly enriched at the larval neuromuscular junction (NMJ) (Fig. S1, A–C) where it is required for structural synaptic plasticity (Packard et al, 2015)
Taken together with our single-molecule FISH (smFISH) data, these results suggest that proper translation of msp300 transcripts in larval muscle requires Syp, but msp300 transcription and cytoplasmic mRNA levels are not regulated by Syp
Summary
Activity-dependent neuronal plasticity is the cellular basis of memory and learning, involving the formation of new synapses and cytoskeletal remodeling in response to neuronal activity (West and Greenberg, 2011). It is thought that neuronal activation leads to the elevated expression of >1,000 different genes. Many activity-dependent genes have been identified through either RNA sequencing studies (Chen et al, 2016) or proteomics analysis (Dieterich and Kreutz, 2016), and the majority of the effort in the field has focused on explaining how altered neural activity leads to changes in gene expression through transcriptional regulation (Madabhushi and Kim, 2018). Posttranscriptional regulation is thought to be a crucial mechanism to explain changes in gene expression in response to neuronal activity. The Nesprins are encoded by genes called synaptic nuclear envelope and -2 (SYNE-1 and -2), which contain ≥80 disease-related variants that cause cerebellar ataxias or muscular dystrophies (Zhou et al, 2018b). The molecular function of Nesprins and their role in muscular diseases are relatively well studied in mouse models of SYNE-1 and SYNE-2 (Zhou et al, 2018a) in relation to nucleocytoplasmic and cytoskeletal organization and function, but the function of Nesprins in neurological disorders is not yet well understood
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