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.
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