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The role of local mRNA translation in synapse formation

Final Report Summary - PRESYNAPTOGENESIS (The role of local mRNA translation in synapse formation)

The mechanism of local protein synthesis in dendrites and axons is currently under intense investigation. Recent studies identified a large number of mRNAs localized at distal axons and growth cones, suggesting that local axonal translation may play an important role in different steps of neuronal development. In line with these evidences, it was demonstrated the requirement of local translation during axon chemotrophic responses to guidance cues. Moreover, it was demonstrated that local axonal translation is required for other neurodevelopmental mechanisms, such as axonal outgrowth, neuronal survival and axon regeneration. Interestingly, recent studies in Aplysia, suggest that local translation might be important for synapse formation. However, the role of local protein synthesis in presynaptic differentiation is largely unknown. Using a novel platform, a microfluidic chamber system which allows the physical separation of axons from cell bodies and dendrites, we were able to specifically manipulate axons without the cell body contribution. Our results demonstrate that FGF22 induced the clustering of synaptic vesicles, a hallmark of presynaptic assembly, when added specifically to axons. Additionally, when protein synthesis is inhibited specifically in axons, SV2 clustering is reduced to basal levels. FGF22 leads to the phosphorylation of 4E-BP1, a translational repressor, in an asymmetric pattern and induces intra-axonal translation of a Beta-actin reporter, a destabilized form of EGFP fused to the 3’UTR of Beta-actin. Moreover, a motor neuron-muscle co-culture suggests that the Beta-actin reporter accumulates at newly formed synapses. Taken together our results show that FGF22 activates cap-dependent translation and that this intra-axonal mRNA translation is required for presynaptic differentiation. We already published four papers with the contribution from this IRG, we have another under revision and we are currently preparing two other papers for publication. I have been hired by the Host Institution after the conclusion of this IRG and the financial support provided by this Grant was essential for that outcome.