BDNF induces translocation of initiation factor 4E to mRNA granules: evidence for a role of synaptic microfilaments and integrins.
In many cell types, translation can be regulated by a redistribution of translation initiation factors to actin-based cytoskeletal compartments that contain bound mRNAs. This process is evoked by extracellular signals and is regulated by determinants of cytoskeletal organization, such as integrins. In the present experiments, we provide evidence that similar mechanisms regulate local translation in dendrites during synaptic plasticity. Treatment of various neuronal preparations with the brain-derived neurotrophic factor (BDNF) resulted in redistribution of the critical eukaryotic initiation factor 4E (eIF4E) to an mRNA granule-rich cytoskeletal fraction isolated from detergent-solubilized samples. eIF4E linkage to cap structures mediates the recruitment of other translation factors in the initiation of translation events. Immunoprecipitation studies confirmed that eIF4E associates with mRNA granules and that BDNF increased this association. BDNF-induced redistribution of eIF4E was blocked by preincubation with either a peptide (GRGDSP) that inhibits integrin-matrix interactions or by a high concentration (20 microM) of the F-actin depolymerizing agent latrunculin A. Immunohistochemical studies in cultured neurons demonstrated that BDNF facilitated translocation of eIF4E into dendritic spines. Together, the findings suggest that BDNF regulates translation in dendrites by altering the localization of eIF4E relative to cytoskeletally bound mRNA granules. Integrins, which are known to be essential for stabilizing certain forms of synaptic plasticity, may be critical regulators of local translation events at synapses.
Smart
Fiona M
FM
Department of Neurobiology, The Scripps Research Institute, and The Skaggs Institute for Chemical Biology, La Jolla, CA 92037, USA.
Edelman
Gerald M
GM
Vanderklish
Peter W
PW
D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D016023:Integrins / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D013347:Subcellular Fractions / Q000378:metabolism; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism*
D000199:Actins; D019208:Brain-Derived Neurotrophic Factor; D039561:Eukaryotic Initiation Factor-4E; D016023:Integrins; D012333:RNA, Messenger; D011994:Recombinant Proteins