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Localised RNA-based mechanisms underlie neuronal wiring

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Our research aims to understand how neural circuits become wired-up properly in the developing brain and how they are maintained into maturity. Emerging evidence points to an increasingly important role for post-translational mechanisms such as RNA localization and local protein synthesis in axons. RNA localization enables nascent proteins to be positioned at precise subcellular locations facilitating localized growth responses to extrinsic signals. Our work has shown that extrinsic signals trigger rapid de novo synthesis in axonal growth cones and that local translation is critical for directional steering. I will present our recent in vivo work using the Axon-TRAP-RiboTag approach in the mouse to analyse mRNA translation in axons (Shigeoka et al, Cell 2016). This study reveals that the young (embryonic-to-postnatal) axonal translatome comprises an evolving subset of enriched genes with axon-specific roles. Adult axons, remarkably, have a complex translatome with strong links to axon survival, neurotransmission, and neurodegenerative disease. I will also present live imaging studies in which simultaneous tracking of RNA granule dynamics and axonal morphology in vivo demonstrates that RNA granules dock at sites of branch emergence and invade stabilised branches (Wong et al, Neuron 2017). The data demonstrate a requirement for local protein synthesis in building arbor complexity and suggest a key role for local translation in neuronal remodelling. Shigeoka T, Jung H, Jung J, Turner-Bridger, B, Ohk J, Lin JQ, Amieux PS, Holt CE. Dynamic axonal translation in developing and mature visual circuits. Cell. Jun 30; 166(1):181-92 (2016). Wong HH, Lin JQ, Ströhl F, Roque CG, Cioni, JM, Cagnetta R, Turner-Bridger B, Laine R, Harris WA, Kaminski CF, Holt CE. RNA docking and local translation regulate site-specific axon remodelling in vivo. Neuron. Aug 16 95(4):852-868.e8. (2017).

This talk is part of the MRC LMB Seminar Series series.

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