Noncanonical Modulation of the eIF2 Pathway Controls an Increase in Local Translation during Neural Wiring.
MetadataShow full item record
Cagnetta, R., Wong, H. H., Frese, C. K., Mallucci, G., Krijgsveld, J., & Holt, C. (2019). Noncanonical Modulation of the eIF2 Pathway Controls an Increase in Local Translation during Neural Wiring.. Molecular cell, 73 (3), 474-489.e5. https://doi.org/10.1016/j.molcel.2018.11.013
Local translation is rapidly regulated by extrinsic signals during neural wiring but its control mechanisms remain elusive. Here, we show that the extracellular cue Sema3A induces an initial burst in local translation that precisely controls the phosphorylation of the translation initiation factor eIF2α via the Unfolded Protein Response (UPR) kinase, PERK. Strikingly, in contrast to canonical UPR signaling, the Sema3A-induced eIF2α phosphorylation bypasses global translational repression and underlies an increase in local translation through differential activity of eIF2B, mediated by Protein Phosphatase 1. Ultrasensitive proteomic analysis on axons reveals 75 proteins translationally controlled via the Sema3A-p-eIF2α pathway. These include proteostasis- and actin cytoskeleton-related proteins, but not canonical stress markers. Finally, we show that PERK signaling is needed for directional axon migration and visual pathway development in vivo. Thus, our findings reveal a noncanonical eIF2 signaling pathway that controls selective changes in axon translation and is required for neural wiring.
Axons, Retinal Ganglion Cells, Animals, Xenopus laevis, eIF-2 Kinase, Eukaryotic Initiation Factor-2B, Xenopus Proteins, Semaphorin-3A, Eukaryotic Initiation Factor-2, Tissue Culture Techniques, Proteomics, Signal Transduction, Phosphorylation, Female, Male, Neurogenesis, Protein Interaction Maps
Wellcome Trust (085314/Z/08/Z)
European Research Council (322817)
Wellcome Trust (203249/Z/16/Z)
ECH2020 EUROPEAN RESEARCH COUNCIL (ERC) (647479)
UK Dementia Research Institute (DRICam17/18)
External DOI: https://doi.org/10.1016/j.molcel.2018.11.013
This record's URL: https://www.repository.cam.ac.uk/handle/1810/286998