Universität zu Köln

Cagnetta, Roberta, Wong, Hovy Ho-Wai, Frese, Christian K., Mallucci, Giovanna R., Krijgsveld, Jeroen and Holt, Christine E. (2019). Noncanonical Modulation of the eIF2 Pathway Controls an Increase in Local Translation during Neural Wiring. Mol. Cell, 73 (3). S. 474 - 495. CAMBRIDGE: CELL PRESS. ISSN 1097-4164

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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 eIF2 alpha via the unfolded protein response (UPR) kinase PERK. Strikingly, in contrast to canonical UPR signaling, Sema3A-induced eIF2 alpha 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 Sema3Ap-eIF2 alpha 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Cagnetta, Roberta UNSPECIFIED UNSPECIFIED UNSPECIFIED Wong, Hovy Ho-Wai UNSPECIFIED UNSPECIFIED UNSPECIFIED Frese, Christian K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mallucci, Giovanna R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Krijgsveld, Jeroen UNSPECIFIED UNSPECIFIED UNSPECIFIED Holt, Christine E. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-156885
DOI:	10.1016/j.molcel.2018.11.013
Journal or Publication Title:	Mol. Cell
Volume:	73
Number:	3
Page Range:	S. 474 - 495
Date:	2019
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1097-4164
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MESSENGER-RNA TRANSLATION; UNFOLDED PROTEIN RESPONSE; CHEMOTROPIC RESPONSES; GROWTH; AXON; DISTINCT; EIF2-ALPHA; STRESS; REQUIREMENT; MAINTENANCE Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15688