Smaug 1 silencing foci respond to NMDA and modulate synaptogenesis

MARÍA VERÓNICA BAEZ; LUCIANA LUCHELLI; DARÍO MASCHI; MARTIN HABIF; GRACIELA L. BOCCACCIO

Saxtons River, VT. Estados Unidos

Conferencia; Summer Research Conference on "Intracellular RNA Transport and Localized Translation"; 2009

FASEB/EMBO

We have previously shown that mammalian Smaug 1 (mSmaug1) represses the translation of reporter mRNAs carrying specific motifs termed Smaug-Recognition-Element (SRE) (Baez and Boccaccio, JBC 2005). Here we show that mSmaug 1 expression is restricted to mature neurons, and occurs simultaneously with the appearance of synaptic components. Smaug1 forms foci that are associated with the post-synapse density and in contact with P-Bodies. Smaug 1 foci size and abundance increase in the presence of polysome-destabilizing drugs, and decrease upon treatment with polysome-stabilizing agents, a typical feature of RNA silencing foci. Furthermore, mSmaug 1 foci located at synapses reversibly disassemble upon neuron depolarization. Pharmacological studies indicate that mSmaug 1 foci dissolution is triggered by NMDA receptor (NMDAR) activation. Dissolution of mSmaug 1 foci upon NMDAR activation is blocked by polysome-disrupting drugs, suggesting that synaptic stimulation provokes the release of silenced mRNAs from mSmaug 1 foci, thus allowing their translation. The mSmaug 1 RNA binding domain is dispensable for foci formation, suggesting that foci formation is not a consequence of binding to silenced mRNAs. The response to NMDAR activation involves PI3K signalling. Finally, we found that mSmaug1 knockdown provokes the formation of smaller and more numerous synapses. In agreement with this defect in synapse morphology, mSmaug 1-depleted neurons respond defectively to a repetitive depolarizing stimulus, as indicated by a reduced induction of ARC, an early gene marker of activity. Our results suggest that mSmaug1 regulates localized translation upon synaptic stimulation, thus affecting synapse biogenesis and/or plasticity.