Dynamic Axonal Translation in Developing and Mature Visual Circuits.

Local mRNA translation mediates the adaptive responses of axons to extrinsic signals, but direct evidence that it occurs in mammalian CNS axons in vivo is scant. We developed an axon-TRAP-RiboTag approach in mouse that allows deep-sequencing analysis of ribosome-bound mRNAs in the retinal ganglion cell axons of the developing and adult retinotectal projection in vivo. The embryonic-to-postnatal axonal translatome comprises an evolving subset of enriched genes with axon-specific roles, suggesting distinct steps in axon wiring, such as elongation, pruning, and synaptogenesis. Adult axons, remarkably, have a complex translatome with strong links to axon survival, neurotransmission, and neurodegenerative disease. Translationally co-regulated mRNA subsets share common upstream regulators, and sequence elements generated by alternative splicing promote axonal mRNA translation. Our results indicate that intricate regulation of compartment-specific mRNA translation in mammalian CNS axons supports the formation and maintenance of neural circuits in vivo. ; This work was supported by Wellcome Trust Programme Grant (085314/Z/08/Z), European Research Council Advanced Grant (322817) to CEH , Cambridge Wellcome Trust PhD programme in Developmental Biology (PMAG/406; BT-B), Gates Cambridge Scholarship (JQL), Basic Science Research Program (2013R1A1A1009625 & 2014K2A7A1036305), Biomedical Technology Development Program (2013M3A9D5072551), & Brain Research Program (2015M3C7A1028396) funded through the NRF by the Korean government (MSIP), Yonsei University Future-leading Research Initiative of 2015 (2015-22-0095), and a faculty research grant from Yonsei University College of Medicine for 2013 (6-2013-0064-2-1) to HJ. ; This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Cell Press.