PRESYNAPTOGENESIS · The role of local mRNA translation in synapse formation
FP7 — People (Marie Curie Actions)
- Duration
- 2010-04-01 → 2014-03-31
- EU contribution
- €100,000
- Participants
- 1
- Scheme
- MC-IRG
Lines connect the coordinator with its partners.
Results in brief
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.
Data: CORDIS, © European Union
Project objective
The objective of the proposed research is to identify the signaling mechanisms that lead to presynaptogenesis, the mechanism by which a functional presynaptic terminal is formed. Postsynaptic mechanisms such as LTF (long-term facilitation) in invertebrate neurons, and LTP (long-term potentiation) and LTD (long-term depression) in mammalian neurons have been well characterized and shown to be dependent on local mRNA translation. However, presynaptic protein synthesis has not been object of intense studies in the past years. Recent studies show that axons can rapidly integrate and respond to local cues by regulating locally protein synthesis. Studies involving axonal protein synthesis in neurodevelopment have focused essentially on the role of local mRNA translation in growth cone collapse. However, recent data has shown that local translation is required for other neurodevelopmental mechanisms like neuronal survival and axonal pathfinding. Also, the observation that distal axons have a diverse mRNA composition leads us to ask if local mRNA translation may play an important role in other neurodevelopmental processes like presynaptic differentiation. In our preliminary studies we addressed this question. We have found that axonal application of FGF22 induces synapse formation in ciliary ganglia motor neurons in culture, as accessed by synapsin clustering. Protein synthesis inhibitors were able to block this effect indicating that local protein translation is required for synapse assembly. However, the mechanisms by which synaptogenic cues lead to the formation of a functional synapse remain unknown. Here we test the hypothesis that presynaptic differentiation occurs through local mRNA translation.
Original text from CORDIS.
Participants
- CENTRO DE NEUROCIENCIAS E BIOLOGIACELULAR ASSOCIACAO · COIMBRACoordinatorPortugal
Links
Data: CORDIS, © European Union