Combined kinesin-1 and kinesin-3 activity drives axonal trafficking of TrkB receptors in Rab6 carriers
Zahavi, Eitan Erez; Hummel, Jessica J.A.; Han, Yuhao; Bar, Citlali; Stucchi, Riccardo; Altelaar, Maarten; Hoogenraad, Casper C.
(2021) Developmental Cell, volume 56, issue 4, pp. 494 - 508.E7
(Article)
Abstract
Neurons depend on proper localization of neurotrophic receptors in their distal processes for their function. The Trk family of neurotrophin receptors controls neuronal survival, differentiation, and remodeling and are well known to function as retrograde signal carriers transported from the distal axon toward the cell body. However, the mechanism driving
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anterograde trafficking of Trk receptors into the axon is not well established. We used microfluidic compartmental devices and inducible secretion assay to systematically investigate the retrograde and anterograde trafficking routes of TrkB receptor along the axon in rat hippocampal neurons. We show that newly synthesized TrkB receptors traffic through the secretory pathway and are directly delivered into axon. We found that these TrkB carriers associate and are regulated by Rab6. Furthermore, the combined activity of kinesin-1 and kinesin-3 is needed for the formation of axon-bound TrkB secretory carriers and their effective entry and processive anterograde transport beyond the proximal axon. Neurons distribute signaling receptors to distal axons to receive extracellular information. Focusing on the neurotrophic receptor TrkB, Zahavi et al. elucidate an intracellular trafficking pathway that enables neurons to drive TrkB from its site of synthesis at the cell body, via secretory transport carriers, into the distal axon.
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Keywords: anterograde transport, axon transport, kinesin-1, kinesin-3, Rab6, RUSH, secretory trafficking, TrkB, Molecular Biology, General Biochemistry,Genetics and Molecular Biology, Developmental Biology, Cell Biology
ISSN: 1534-5807
Publisher: Cell Press
Note: Funding Information: We thank Prof. Frederic Saudou and Amelie Grenoux from Grenoble Institute for Neuroscience for providing the molds and the training for the production of the microfluidic devices used in this study. We thank Dr. Maud Martin for kindly providing guidance, plasmids, and reagents for the RUSH experiments. This work was supported by EMBO Long-Term Fellowship (EMBO-LTF, E.E.Z.), the Netherlands Organization for Scientific Research (NWO-ALW-VICI, 865.10.010 , C.C.H.), the Netherlands Organization for Health Research and Development (ZonMw-TOP, 912.16.058 , C.C.H.), the European Research Council (ERC) (ERC-consolidator, 617050 , C.C.H.). Funding Information: We thank Prof. Frederic Saudou and Amelie Grenoux from Grenoble Institute for Neuroscience for providing the molds and the training for the production of the microfluidic devices used in this study. We thank Dr. Maud Martin for kindly providing guidance, plasmids, and reagents for the RUSH experiments. This work was supported by EMBO Long-Term Fellowship (EMBO-LTF, E.E.Z.), the Netherlands Organization for Scientific Research (NWO-ALW-VICI, 865.10.010, C.C.H.), the Netherlands Organization for Health Research and Development (ZonMw-TOP, 912.16.058, C.C.H.), the European Research Council (ERC) (ERC-consolidator, 617050, C.C.H.). E.E.Z. initiated the study, designed and performed experiments, analyzed and formatted data for presentation in the manuscript, and wrote the manuscript. J.J.A.H. established experimental procedure, performed experiments, and guided experimental work. Y.H. and C.B. performed experimental work. R.S. performed the mass spectrometry experiment and analysis. M.A. gave valuable advice on mass spectrometry; C.C.H. designed the overall experimental plan, supervised the research, and wrote the manuscript. All authors contributed to the formatting and editing of the manuscript. C.C.H. is an employee of Genentech, a member of the Roche group. The authors declare no additional competing interests. Publisher Copyright: © 2021 The Authors Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
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