title: Growth cone MKK7 mRNA targeting regulates MAP1b-dependent microtubule bundling to control neurite elongation.
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.
authors.affiliation: Institute for Biochemistry and Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Feltrin
authors.forename: Ludovico
authors.initials: L
authors.lastname: Fusco
authors.forename: Harald
authors.initials: H
authors.lastname: Witte
authors.forename: Francesca
authors.initials: F
authors.lastname: Moretti
authors.forename: Katrin
authors.initials: K
authors.lastname: Martin
authors.forename: Michel
authors.initials: M
authors.lastname: Letzelter
authors.forename: Erika
authors.initials: E
authors.lastname: Fluri
authors.forename: Peter
authors.initials: P
authors.lastname: Scheiffele
authors.forename: Olivier
authors.initials: O
authors.lastname: Pertz
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D002460:Cell Line; D016678:Genome / Q000235:genetics; D020439:Growth Cones / Q000201:enzymology*; D006624:Hippocampus / Q000166:cytology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048688:MAP Kinase Kinase 7 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D008954:Models, Biological; D016501:Neurites / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism; D014176:Protein Biosynthesis; D034443:RNA Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D013997:Time Factors
chemical_list: D020413:3' Untranslated Regions; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; C085284:microtubule-associated protein 1B; D010769:Phosphothreonine; D048031:JNK Mitogen-Activated Protein Kinases; D048688:MAP Kinase Kinase 7; C482570:Map2k7 protein, mouse