Growth cone MKK7 mRNA targeting regulates MAP1b-dependent microtubule bundling to control neurite elongation

Daniel Feltrin; Ludovico Fusco; Harald Witte; Francesca Moretti; Katrin Martin; Michel Letzelter; Erika Fluri; Peter Scheiffele; Olivier Pertz

doi:10.1371/journal.pbio.1001439

Growth cone MKK7 mRNA targeting regulates MAP1b-dependent microtubule bundling to control neurite elongation

PLoS Biol. 2012;10(12):e1001439. doi: 10.1371/journal.pbio.1001439. Epub 2012 Dec 4.

Authors

Daniel Feltrin¹, Ludovico Fusco, Harald Witte, Francesca Moretti, Katrin Martin, Michel Letzelter, Erika Fluri, Peter Scheiffele, Olivier Pertz

Affiliation

¹ Institute for Biochemistry and Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.

Abstract

Local mRNA translation in neurons has been mostly studied during axon guidance and synapse formation but not during initial neurite outgrowth. We performed a genome-wide screen for neurite-enriched mRNAs and identified an mRNA that encodes mitogen-activated protein kinase kinase 7 (MKK7), a MAP kinase kinase (MAPKK) for Jun kinase (JNK). We show that MKK7 mRNA localizes to the growth cone where it has the potential to be translated. MKK7 is then specifically phosphorylated in the neurite shaft, where it is part of a MAP kinase signaling module consisting of dual leucine zipper kinase (DLK), MKK7, and JNK1. This triggers Map1b phosphorylation to regulate microtubule bundling leading to neurite elongation. We propose a model in which MKK7 mRNA localization and translation in the growth cone allows for a mechanism to position JNK signaling in the neurite shaft and to specifically link it to regulation of microtubule bundling. At the same time, this uncouples activated JNK from its functions relevant to nuclear translocation and transcriptional activation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions / genetics
Animals
Base Sequence
Cell Differentiation
Cell Line
Genome / genetics
Growth Cones / enzymology*
Hippocampus / cytology
JNK Mitogen-Activated Protein Kinases / metabolism
MAP Kinase Kinase 7 / metabolism*
MAP Kinase Signaling System
Mice
Microtubule-Associated Proteins / metabolism*
Microtubules / metabolism*
Models, Biological
Neurites / enzymology
Neurites / metabolism*
Phosphorylation
Phosphothreonine / metabolism
Protein Biosynthesis
RNA Transport*
RNA, Messenger / genetics
RNA, Messenger / metabolism
Reproducibility of Results
Time Factors

Substances

3' Untranslated Regions
Microtubule-Associated Proteins
RNA, Messenger
microtubule-associated protein 1B
Phosphothreonine
JNK Mitogen-Activated Protein Kinases
MAP Kinase Kinase 7
Map2k7 protein, mouse

Grants and funding

Swiss National Science Foundation (http://www.snf.ch) International Research Foundation for Paraplegy (http://www.irp.ch). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.