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

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Cagnetta, Roberta 
Wong, Hovy Ho-Wai 
Frese, Christian K 
Mallucci, Giovanna R 
Krijgsveld, Jeroen 

Abstract

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.

Description

Keywords

PERK, Sema3A, axon, axon branching, axon guidance, eIF2B, eIF2α, local translation, retinal ganglion cell, unfolded protein response, Animals, Axons, Eukaryotic Initiation Factor-2, Eukaryotic Initiation Factor-2B, Female, Male, Neurogenesis, Phosphorylation, Protein Interaction Maps, Proteomics, Retinal Ganglion Cells, Semaphorin-3A, Signal Transduction, Tissue Culture Techniques, Xenopus Proteins, Xenopus laevis, eIF-2 Kinase

Journal Title

Mol Cell

Conference Name

Journal ISSN

1097-2765
1097-4164

Volume Title

73

Publisher

Elsevier BV
Sponsorship
Wellcome Trust (085314/Z/08/Z)
European Research Council (322817)
Wellcome Trust (203249/Z/16/Z)
BBSRC (1366878)
European Research Council (647479)
UK Dementia Research Institute (DRICam17/18)