Dynamics of mRNA-silencing foci at the synapse

LUCHELLI L; MASCHI D; PASCUAL M; FERNANDEZ-ALVAREZ AJ; THOMAS MG; BOCCACCIO G.L

Niagara-on-the-Lake, Ontario

Conferencia; 10 th International conference Intracellular RNA localization and Localized Translation; 2013

Unversity of Toronto

The local production of proteins that ultimately control the synapse strength is modulated by synaptic activity. Translation regulation is frequently linked to the dynamic assembly of mRNA-silencing foci, which are macromolecular aggregates of repressed mRNPs that eventually disassemble to release transcript thus allowing translation. We have previously identified a kind of mRNA-silencing foci specific of neurons, termed S-foci, as they contain the regulator Smaug1/SAMD4a, which affects synaptogenesis and the synapse response (Baez et al. J Biol Chem 2005; J Cell Biol 2011; Perez Pepe et al. PLoS One 2012). Here we compare the dynamics of the S-foci, Processing Bodies (PBs) and FMRP granules upon synaptic activation and find that different stimuli differentially affect their integrity. NMDAR activation induces the rapid and transient dissolution of the S-foci, whereas a subset of PBs displays an opposite response and their presence in the synapse surroundings slowly increases. FMRP granules do not respond to NMDA, but dissolve upon AMPAR stimulation, which does not affect the S-foci. Metabotropic receptor stimulation induces the transient dissolution of the three foci with different kinetics, rapidly affecting FMRP granules and S-foci and slowly provoking the disassembly of a subset of PBs. We analyzed local protein synthesis by the FUNCAT strategy and find that NMDA provokes a global silencing whereas DHPG enhances local translation rapidly. Collectively, these observations suggest that specific mRNAs are controlled upon synaptic stimulation by specific foci independently of the global effects on translation. The S-foci apparently regulates CamKII mRNA and recent results indicate that Smaug1 also affects Nanos 1. We propose the collective name of synaptic activity-regulated mRNA silencing (SyAS) foci for these RNP aggregates that selectively respond to distinct stimulation patterns and contribute to the fine-tuning of local protein synthesis at the synapse (Pascual et al., CIB 2012).