Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Sep:91:25-33.
doi: 10.1016/j.mcn.2018.03.013. Epub 2018 Mar 27.

Mechanisms of neurotrophin trafficking via Trk receptors

Emily Scott-Solomon  1 , Rejji Kuruvilla  2
Affiliations
Review

Mechanisms of neurotrophin trafficking via Trk receptors

Emily Scott-Solomon et al. Mol Cell Neurosci. 2018 Sep.

Abstract

In neurons, long-distance communication between axon terminals and cell bodies is a critical determinant in establishing and maintaining neural circuits. Neurotrophins are soluble factors secreted by post-synaptic target tissues that retrogradely control axon and dendrite growth, survival, and synaptogenesis of innervating neurons. Neurotrophins bind Trk receptor tyrosine kinases in axon terminals to promote endocytosis of ligand-bound phosphorylated receptors into signaling endosomes. Trk-harboring endosomes function locally in axons to acutely promote growth events, and can also be retrogradely transported long-distances to remote cell bodies and dendrites to stimulate cytoplasmic and transcriptional signaling necessary for neuron survival, morphogenesis, and maturation. Neuronal responsiveness to target-derived neurotrophins also requires the precise axonal targeting of newly synthesized Trk receptors. Recent studies suggest that anterograde delivery of Trk receptors is regulated by retrograde neurotrophin signaling. In this review, we summarize current knowledge on the functions and mechanisms of retrograde trafficking of Trk signaling endosomes, and highlight recent discoveries on the forward trafficking of nascent receptors.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Retrograde Trk signaling endosomes regulate diverse developmental events in multiple neuronal compartments
(a) In axon terminals, NGF promotes endocytosis of its TrkA receptors by activating a signaling pathway that involves PLCγ1, calcineurin, and dynamin1. NGF-TrkA-containing signaling endosomes promote local growth events and are also retrogradely transported back to neuronal soma. TrkA endosomal signaling controls its own vesicular trafficking by stimulating breakdown of a dense actin meshwork in axon terminals. (b) Activated Trk receptors are transported along axonal microtubules in endosomes, positive for Rab5 or Rab7, by dynein motors. Trk receptors interact with dynein motors either directly or indirectly via adaptors. Trk signaling actively recruits dynein motors via phosphorylation of dynein intermediate chains. (c) In cell bodies, axon-derived Trk endosomes are exocytosed to soma surfaces where they interact with nascent receptors to influence their forward trafficking to axons (transcytosis). Persistent Trk signaling may be facilitated by Coronin-1-mediated local recycling, which allows receptors to evade lysosomal fusion and degradation. (d) Somatic signaling by Trk endosomes activates transcriptional programs necessary for survival and growth. (e) A sub-set of axon-derived Trk endosomes signal locally in dendrites to modulate the assembly of post-synaptic components.
Figure 2
Figure 2. Mechanisms for anterograde delivery of Trk receptors
(a) Constitutive delivery of Trk receptors to axons via the secretory pathway. Exit of Trk receptors from the trans-Golgi-network may be mediated by interactions with sortilin, and its binding partner, ARHGAP33. (b) Anterograde transport of Trk receptors in secretory vesicles that are positive for Rab3 or Rab27B, mediated by kinesin motors, KIF1A or Kinesin-1. Trk receptors are coupled to kinesin motors with the help of adaptors such as Slp1, CRMP-2, JIP1 or JIP3. (c) In addition to the canonical secretory pathway, Trk receptors undergo axonal targeting via transcytosis, where soma surface-resident receptors are internalized and transported to axons in Rab11-positive recycling endosomes. Retrograde NGF signaling is necessary for anterograde transcytosis of TrkA receptors. Active axon-derived TrkA receptors are inserted on soma surfaces where they elicit phosphorylation and subsequent endocytosis of naive soma surface receptors. Endocytosed receptors are dephosphorylated by PTP1B, an Endoplasmic Reticulum-resident protein tyrosine phosphatase, to ensure axon targeting of inactive receptors to engage with ligand at terminals.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Andreassi C, Zimmermann C, Mitter R, Fusco S, De Vita S, Saiardi A, Riccio A. An NGF-responsive element targets myo-inositol monophosphatase-1 mRNA to sympathetic neuron axons. Nature neuroscience. 2010;13:291–301. - PubMed
    1. Arimura N, Kimura T, Nakamuta S, Taya S, Funahashi Y, Hattori A, Shimada A, Menager C, Kawabata S, Fujii K, et al. Anterograde transport of TrkB in axons is mediated by direct interaction with Slp1 and Rab27. Developmental cell. 2009;16:675–686. - PubMed
    1. Ascano M, Bodmer D, Kuruvilla R. Endocytic trafficking of neurotrophins in neural development. Trends in cell biology. 2012;22:266–273. - PMC - PubMed
    1. Ascano M, Richmond A, Borden P, Kuruvilla R. Axonal targeting of Trk receptors via transcytosis regulates sensitivity to neurotrophin responses. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2009;29:11674–11685. - PMC - PubMed
    1. Atwal JK, Massie B, Miller FD, Kaplan DR. The TrkB-Shc site signals neuronal survival and local axon growth via MEK and P13-kinase. Neuron. 2000;27:265–277. - PubMed

Publication types

Substances