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

Roberta Cagnetta, Hovy Ho-Wai Wong, Christian K Frese, Giovanna Mallucci, Jeroen Krijgsveld, Christine Holt, Apollo-University Of Cambridge Repository, Apollo-University Of Cambridge Repository
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
more » ... erlies 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.
doi:10.17863/cam.34307 fatcat:sgpjjem3nnfkvpciqdxk3mw6r4