Multivesicular bodies mediate long-range retrograde NGF-TrkA signaling

Abstract
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Abstract

The development of neurons in the peripheral nervous system is dependent on target-derived, long-range retrograde neurotrophic factor signals. The prevailing view is that target-derived nerve growth factor (NGF), the prototypical neurotrophin, and its receptor TrkA are carried retrogradely by early endosomes, which serve as TrkA signaling platforms in cell bodies. Here, we report that the majority of retrograde TrkA signaling endosomes in mouse sympathetic neurons are ultrastructurally- and molecularly-defined multivesicular bodies (MVBs). In contrast to MVBs that carry non-TrkA cargoes from distal axons to cell bodies, retrogradely transported TrkA⁺ MVBs that arrive in cell bodies evade lysosomal fusion and instead evolve into TrkA⁺ single-membrane vesicles that are signaling competent. Moreover, TrkA kinase activity associated with retrogradely transported TrkA⁺ MVBs determines TrkA⁺ endosome evolution and fate. Thus, MVBs deliver long-range retrograde NGF signals and serve as signaling and sorting platforms in the cell soma, and MVB cargoes dictate their vesicular fate.

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Author details

Mengchen Ye

Human Genetics Training Program, Johns Hopkins University, Baltimore, United States

Competing interests
No competing interests declared.
Kathryn M Lehigh

Human Genetics Training Program, Johns Hopkins University, Baltimore, United States

Competing interests
No competing interests declared.
David D Ginty

Department of Neurobiology, Harvard Medical School, Boston, United States

For correspondence
david_ginty@hms.harvard.edu

Competing interests
David D Ginty, Reviewing editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0001-9723-8530

Funding

Howard Hughes Medical Institute

David D Ginty

National Institute of Neurological Disorders and Stroke

David D Ginty

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

Moses V Chao, New York University Langone Medical Center, United States

Ethics

Animal experimentation: Mice were handled and housed in accordance with Harvard Medical School IACUC guidelines and described in protocol number 05041.

Version history

Received: October 22, 2017
Accepted: January 30, 2018
Accepted Manuscript published: January 30, 2018 (version 1)
Version of Record published: February 13, 2018 (version 2)

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.