Noncanonical Modulation of the eIF2 Pathway Controls an Increase in Local Translation during Neural Wiring.

Summary 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 phosphorylation of the translation initiation factor eIF2α via the unfolded protein response (UPR) kinase PERK. Strikingly, in contrast to canonical UPR signaling, 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 proteomics analysis of 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. Graphical Abstract Highlights • eIF2α phosphorylation underlies Sema3A-induced upregulation of global translation • pSILAC-SP3 reveals 75 nascent proteins regulated by the Sema3A-p-eIF2α pathway • eIF2B modulation is the key node between Sema3A and canonical stress responses • PERK signaling is required for axon guidance and neural connectivity Cagnetta et al. find that Sema3A triggers phosphorylation of eIF2α in axons through an initial wave of local protein synthesis. eIF2α phosphorylation upregulates global translation via differential eIF2B activity and is required for neural wiring. Proteomics analysis identifies the axonal translational changes regulated by the Sema3A-p-eIF2α pathway. [ABSTRACT FROM AUTHOR]