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

Molecular cell | 2019

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.

Pubmed ID: 30595434 RIS Download

Research resources used in this publication

Associated grants

  • Agency: Wellcome Trust, United Kingdom
  • Agency: Wellcome Trust, United Kingdom
    Id: 203249/Z/16/Z

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This is a list of tools and resources that we have found mentioned in this publication.


ProteomeXchange (tool)

RRID:SCR_004055

A data repository for proteomic data sets. The ProteomeExchange consortium, as a whole, aims to provide a coordinated submission of MS proteomics data to the main existing proteomics repositories, as well as to encourage optimal data dissemination. ProteomeXchange provides access to a number of public databases, and users can access and submit data sets to the consortium's PRIDE database and PASSEL/PeptideAtlas.

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PRISM (tool)

RRID:SCR_005375

THIS RESOURCE IS NO LONGER IN SERVICE. Documented on May 5,2022.Tool that predicts interactions between transcription factors and their regulated genes from binding motifs. Understanding vertebrate development requires unraveling the cis-regulatory architecture of gene regulation. PRISM provides accurate genome-wide computational predictions of transcription factor binding sites for the human and mouse genomes, and integrates the predictions with GREAT to provide functional biological context. Together, accurate computational binding site prediction and GREAT produce for each transcription factor: 1. putative binding sites, 2. putative target genes, 3. putative biological roles of the transcription factor, and 4. putative cis-regulatory elements through which the factor regulates each target in each functional role.

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Promega (tool)

RRID:SCR_006724

An Antibody supplier

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QIAGEN (tool)

RRID:SCR_008539

A commercial organization which provides assay technologies to isolate DNA, RNA, and proteins from any biological sample. Assay technologies are then used to make specific target biomolecules, such as the DNA of a specific virus, visible for subsequent analysis.

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LIMMA (tool)

RRID:SCR_010943

Software package for the analysis of gene expression microarray data, especially the use of linear models for analyzing designed experiments and the assessment of differential expression.

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ATF4 antibody (antibody)

RRID:AB_1861369

This polyclonal targets ATF4

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Monoclonal Anti-alpha-Tubulin antibody produced in mouse (antibody)

RRID:AB_477582

This monoclonal targets alpha-Tubulin antibody produced in mouse

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Slit1 antibody (antibody)

RRID:AB_10903854

This polyclonal targets Slit1 antibody

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Gelsolin antibody (antibody)

RRID:AB_2295090

This polyclonal targets Gelsolin

View all literature mentions

eIF2B epsilon antibody (antibody)

RRID:AB_2230901

This polyclonal targets Human eIF2B epsilon

View all literature mentions

Anti-Puromycin Antibody, clone 12D10 (antibody)

RRID:AB_2566826

This monoclonal targets Puromycin from Streptomyces alboniger

View all literature mentions

Anti-RPL7A antibody (antibody)

RRID:AB_2736874

This unknown targets RPL7A

View all literature mentions

PERK (C33E10) Rabbit mAb (antibody)

RRID:AB_2095847

This monoclonal targets PERK (C33E10) Rabbit mAb

View all literature mentions

Phosphorylated eukaryotic translation initiation factor 2 subunit 1 (antibody)

RRID:AB_732117

This monoclonal targets A synthetic phospho-peptide corresponding to residues surrounding Ser51 of human EIF2S1.

View all literature mentions

Anti-EIF2S1 antibody (antibody)

RRID:AB_2736873

This polyclonal targets EIF2S1

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GraphPad Prism (software resource)

RRID:SCR_002798

Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.

View all literature mentions

STRING (data or information resource)

RRID:SCR_005223

Database of known and predicted protein interactions. The interactions include direct (physical) and indirect (functional) associations and are derived from four sources: Genomic Context, High-throughput experiments, (Conserved) Coexpression, and previous knowledge. STRING quantitatively integrates interaction data from these sources for a large number of organisms, and transfers information between these organisms where applicable. The database currently covers 5''214''234 proteins from 1133 organisms. (2013)

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DAVID (software resource)

RRID:SCR_001881

Bioinformatics resource system including web server and web service for functional annotation and enrichment analyses of gene lists. Consists of comprehensive knowledgebase and set of functional analysis tools. Includes gene centered database integrating heterogeneous gene annotation resources to facilitate high throughput gene functional analysis.

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Perseus (software resource)

RRID:SCR_015753

Software that supports biological and biomedical researchers in interpreting protein quantification, interaction and post-translational modification data. Perseus contains a comprehensive portfolio of statistical tools for high-dimensional omics data analysis covering normalization, pattern recognition, time-series analysis, cross-omics comparisons and multiplehypothesis testing.

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MaxQuant (software resource)

RRID:SCR_014485

A quantitative proteomics software package for analyzing large-scale mass-spectrometric data sets. It is a set of algorithms that include peak detection and scoring of peptides, mass calibration, database searches for protein identification, protein quantification, and provides summary statistics.

View all literature mentions

KEGG (software resource)

RRID:SCR_012773

Integrated database resource consisting of 16 main databases, broadly categorized into systems information, genomic information, and chemical information. In particular, gene catalogs in completely sequenced genomes are linked to higher-level systemic functions of cell, organism, and ecosystem. Analysis tools are also available. KEGG may be used as reference knowledge base for biological interpretation of large-scale datasets generated by sequencing and other high-throughput experimental technologies.

View all literature mentions

Volocity 3D Image Analysis Software (software resource)

RRID:SCR_002668

3D image analysis software to visualize, analyze and validate 3D fluorescence images from a wide range of confocal microscopy, widefield and high content screening systems. It is fully integrated for a seamless user experience.

View all literature mentions

ImageJ (software resource)

RRID:SCR_003070

Open source Java based image processing software program designed for scientific multidimensional images. ImageJ has been transformed to ImageJ2 application to improve data engine to be sufficient to analyze modern datasets.

View all literature mentions

Anti-Puromycin Antibody, clone 12D10 (antibody)

RRID:AB_2566826

This monoclonal targets Puromycin from Streptomyces alboniger

View all literature mentions

GraphPad Prism (software resource)

RRID:SCR_002798

Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.

View all literature mentions

DAVID (software resource)

RRID:SCR_001881

Bioinformatics resource system including web server and web service for functional annotation and enrichment analyses of gene lists. Consists of comprehensive knowledgebase and set of functional analysis tools. Includes gene centered database integrating heterogeneous gene annotation resources to facilitate high throughput gene functional analysis.

View all literature mentions

STRING (data or information resource)

RRID:SCR_005223

Database of known and predicted protein interactions. The interactions include direct (physical) and indirect (functional) associations and are derived from four sources: Genomic Context, High-throughput experiments, (Conserved) Coexpression, and previous knowledge. STRING quantitatively integrates interaction data from these sources for a large number of organisms, and transfers information between these organisms where applicable. The database currently covers 5''214''234 proteins from 1133 organisms. (2013)

View all literature mentions

Anti-EIF2S1 antibody (antibody)

RRID:AB_2736873

This polyclonal targets EIF2S1

View all literature mentions

Phosphorylated eukaryotic translation initiation factor 2 subunit 1 (antibody)

RRID:AB_732117

This monoclonal targets A synthetic phospho-peptide corresponding to residues surrounding Ser51 of human EIF2S1.

View all literature mentions

Volocity 3D Image Analysis Software (software resource)

RRID:SCR_002668

3D image analysis software to visualize, analyze and validate 3D fluorescence images from a wide range of confocal microscopy, widefield and high content screening systems. It is fully integrated for a seamless user experience.

View all literature mentions

Slit1 antibody (antibody)

RRID:AB_10903854

This polyclonal targets Slit1 antibody

View all literature mentions

PERK (C33E10) Rabbit mAb (antibody)

RRID:AB_2095847

This monoclonal targets PERK (C33E10) Rabbit mAb

View all literature mentions

MaxQuant (software resource)

RRID:SCR_014485

A quantitative proteomics software package for analyzing large-scale mass-spectrometric data sets. It is a set of algorithms that include peak detection and scoring of peptides, mass calibration, database searches for protein identification, protein quantification, and provides summary statistics.

View all literature mentions

ImageJ (software resource)

RRID:SCR_003070

Open source Java based image processing software program designed for scientific multidimensional images. ImageJ has been transformed to ImageJ2 application to improve data engine to be sufficient to analyze modern datasets.

View all literature mentions

KEGG (software resource)

RRID:SCR_012773

Integrated database resource consisting of 16 main databases, broadly categorized into systems information, genomic information, and chemical information. In particular, gene catalogs in completely sequenced genomes are linked to higher-level systemic functions of cell, organism, and ecosystem. Analysis tools are also available. KEGG may be used as reference knowledge base for biological interpretation of large-scale datasets generated by sequencing and other high-throughput experimental technologies.

View all literature mentions

Anti-RPL7A antibody (antibody)

RRID:AB_2736874

This unknown targets RPL7A

View all literature mentions

ATF4 antibody (antibody)

RRID:AB_1861369

This polyclonal targets ATF4

View all literature mentions

Monoclonal Anti-alpha-Tubulin antibody produced in mouse (antibody)

RRID:AB_477582

This monoclonal targets alpha-Tubulin antibody produced in mouse

View all literature mentions

Perseus (software resource)

RRID:SCR_015753

Software that supports biological and biomedical researchers in interpreting protein quantification, interaction and post-translational modification data. Perseus contains a comprehensive portfolio of statistical tools for high-dimensional omics data analysis covering normalization, pattern recognition, time-series analysis, cross-omics comparisons and multiplehypothesis testing.

View all literature mentions

Gelsolin antibody (antibody)

RRID:AB_2295090

This polyclonal targets Gelsolin

View all literature mentions

eIF2B epsilon antibody (antibody)

RRID:AB_2230901

This polyclonal targets Human eIF2B epsilon

View all literature mentions